KR20160098475A - N1-(3,3,3-trifluoro-2-hydroxo-2-methylpropionyl)-piperidine derivative as inhibitors of pyruvate dehydrogenase kinase - Google Patents

Abstract

[식 중, R, R¹ 및 R³ 은 청구항 제 1 항에 제시된 의미를 가짐]
은, 피루베이트 데히드로게나아제 키나아제 (PDHK) 의 저해제로, 이는 특히 암과 같은 질병 치료에 이용될 수 있다.Compounds of formula (I)

Wherein R, R < ¹ > and R < ³ > have the meanings given in claim 1,
Is an inhibitor of pyruvate dehydrogenase kinase (PDHK), which can be used for the treatment of diseases such as cancer in particular.

Description

N1- (3,3,3-trifluoro-2-hydroxo-2-methylpropionyl) -piperidine derivative as an inhibitor of pyruvate dehydrogenase kinase {N1- (3,3,3-TRIFLUORO -2-HYDROXO-2-METHYLPROPIONYL) -PIPERIDINE DERIVATIVE AS INHIBITORS OF PYRUVATE DEHYDROGENASE KINASE}

The present invention relates to novel piperidine derivatives which inhibit pyruvate dehydrogenase kinase (PDHK), pharmaceutical compositions comprising them, their preparation and their use in therapy for the treatment of cancer.

Pyruvate dehydrogenase kinase (also pyruvate dehydrogenase complex kinase, PDC kinase, or PDHK) is a kinase enzyme that acts to inactivate enzyme pyruvate dehydrogenase by phosphorylation using ATP.

Thus, PDHK participates in the regulation of pyruvate dehydrogenase complex, the first component of pyruvate dehydrogenase. Both PDHK and pyruvate dehydrogenase complexes are present in the mitochondrial matrix of eukaryotes. The complex acts to convert pyruvate (the product of the corresponding action in the cytosol) to acetyl-coA in the process of citric acid circulation and then generate energy by oxidizing it in mitochondria. By down-regulating the activity of the complex, PDHK will decrease the oxidation of pyruvate in mitochondria and increase the conversion of pyruvate to lactate in the cytoplasm.

The opposite action of PDHK, i. E., Dephosphorylation and activation of pyruvate dehydrogenase, is catalyzed by phosphorylated protein phosphatase, called pyruvate dehydrogenase phosphatase.

(Do not confuse pyruvate dehydrogenase kinase with phosphoinositide-dependent kinase-1, often also known as "PDK1 ").

There are four known PDHK isoenzymes in humans: PDHK1 - PDHK4.

Some studies have shown that insulin-deficient (or insensitive to insulin) cells overexpress PDHK4. As a result, the pyruvate formed from the action can not be oxidized and causes hyperglycemia because glucose in the blood can not be used efficiently. Thus, some drugs target PDHK4 for the treatment of type II diabetes.

PDHK1 has been reported to have increased activity in hypoxic cancer cells due to the presence of HIF-1. PDHK1 releases pyruvate from the citric acid circulation pathway to keep hypoxic cells alive. Thus, PDHK1 inhibits apoptosis in these cancer cells, and thus PDHK1 inhibition has been proposed as an anticancer therapy. Similarly, PDHK3 has been found to be overexpressed in colon cancer cell lines. Three proposed inhibitors are AZD7545 and dichloroacetate, which bind to PDHK1, and Radicicol, which binds PDHK3.

Increasing the active form of PDC by inhibiting PDHK activity is a drug target for diabetes, heart disease and cancer.

EP 2 345 629 A1 discloses a pharmaceutical composition useful for the treatment or prevention of a disease associated with glucose utilization disorders such as diabetes (e.g., type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia and hyperlipemia PDHK < / RTI > Furthermore, PDHK inhibitors are considered useful in the treatment or prevention of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract, etc.). Moreover, PDHK inhibitors are considered useful in the treatment or prevention of diseases caused by limited energy substrate supply to the tissues, such as heart failure, cardiomyopathy, myocardial ischemia, dyslipidemia and atherosclerosis. In addition, PDHK inhibitors are considered useful for the treatment or prevention of cerebral ischemia or stroke. In addition, PDHK inhibitors are considered useful for the treatment or prevention of mitochondrial diseases, mitochondrial myopathies, cancer, and the like. It is also considered to be useful for the treatment or prevention of pulmonary hypertension.

literature:

Wikipedia, pyruvate dehydrogenase kinase;

T.E. Roche et al., Cell. Mol. Life Sci. 64 (2007) 830-849;

A. Kumar et al., Chemico-Biological Interactions 199 (2012) 29-37;

I.Papandreou et al., Int. J. Cancer: 128, 1001-1008 (2011);

G. Sutendra et al., In frontiers in oncology, 2013, vol. 3, 1-11.

It is an object of the present invention to find novel compounds having valuable characteristics, in particular novel compounds which can be used in the manufacture of medicaments.

The compounds according to the invention and their salts have been found to be well tolerated and have very valuable pharmacokinetic properties.

Specifically, the present invention relates to compounds of formula (I) inhibiting PDHK, preferably PDHK2, compositions comprising these compounds, and methods of using the same for the treatment of PDHK-induced diseases and complications.

The compounds of formula I may further be used for the investigation and isolation of the activity or expression of PDHK. Furthermore, they are particularly suitable for use in diagnostic methods of diseases associated with unregulated or impaired PDHK activity.

The host or patient can be any mammalian species, for example a primate species, especially a human; Rodents including mice, rats and hamsters; rabbit; Horses, cows, dogs, cats, and the like. Animal models are important for experimental studies that provide models for the treatment of human diseases.

The specific cell sensitivity to treatment with the compounds according to the invention can be determined by in vitro tests. Typically, the culture medium of the cells is combined with a compound according to the present invention at various concentrations, for a period of time sufficient to induce a cellular response such as the expression of surface markers, such as anti-IgM, for about 1 hour to 1 week . An in vitro test can be performed using cells cultured from blood or biopsy samples. The amount of expressed surface marker is assessed by a flow cytometer using a specific antibody that recognizes the marker.

The dose will vary depending upon the particular compound employed, the particular disease, the condition of the patient, and the like. Therapeutic doses are typically sufficient to significantly reduce undesirable cell populations in the target tissue, while maintaining patient viability. Therapy generally lasts until significant reductions occur, e. G., By about 50% or more reduction in cell burden, and essentially until undesirable cells are no longer detected in the body have.

Prior Art

Fluorene derivatives are described in EP 2 345 629 A1 as PDHK inhibitors for the treatment of diseases such as diabetes and cancer.

Other pyrazole derivatives used as TGR5 agonists are disclosed in WO 2012/082947.

The preparation of pyrazolylaminopyrimidine derivatives used as LRRK2 modulators is described in WO < RTI ID = 0.0 >

Preparation of phenylmethyl-piperidinyl-triazolyl-pyridinyl-indazole derivatives used as ERK inhibitors is described in WO-A-2012/058127.

Preparation of substituted pyrazoles and triazoles as novel prolyl carboxypeptidase inhibitors is described in WO 2011/143057.

Substituted piperidinyl thiazole derivatives and analogues for the treatment of diabetes and metabolic disorders are disclosed in WO 2008/083238.

Heteroarylpyrazoles as p38 kinase inhibitors are described in US 6,979, 686 B1.

Summary of the Invention

The present invention relates to compounds of formula (I), and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures thereof in all ratios:

[Wherein,

R is pyrazol-diyl, imidazol-diyl, isoxazol-diyl or triazol-diyl, each of which is unsubstituted or monosubstituted with R ² ,

R ¹ represents (CH ₂ ) _n Ar, (CH ₂ ) _n Het, A or Cyc,

R ² represents A ', methoxy, hydroxymethyl, COOA', CN, COOH, CONH ₂ or OH,

R ³ represents H, A ', COOA' or CN,

Ar is phenyl, which is unsubstituted, or Hal, A, CN, OA, [C (R 5) 2] p OH, [C (R 5) 2] p N (R 5) 2, NO 2, [C ^{_{(R 5) 2] p COOR}} 5, NR 5 COA, NR 5 SO 2 A, [C (R 5) 2] p SO 2 n (R 5) 2, S (O) n A, O [C (R ^{_{5) 2] m N (R}} 5) 2, NR 5 COOA, NR 5 CON (R 5) 2 , and / or mono to COA -, di-, tri-, tetra- or penta-substituted,

Het is 1 to 4 N, O and / or mono with a S atom-or bicyclic saturated, unsaturated or aromatic heterocycle, which is unsubstituted, or Hal, A, CN, OA, [C (R 5) 2 _{] p OH, [C (R} 5) 2] p N (R 5) 2, NO 2, [C (R 5) 2] p COOR 5, NR 5 COA, NR 5 SO 2 A, [C (R 5 _{) 2] p SO 2 N (} R 5) 2, S (O) n A, O [C (R 5) 2] m N (R 5) 2, NR 5 COOA, NR 5 CON (R 5) 2 , and / RTI > and / or < RTI ID = 0.0 > COA,

Cyc Is cyclic alkyl having 3, 4, 5, 6 or 7 C atoms, which is unsubstituted or mono-substituted with OH,

Wherein A represents a non-branched or branched alkyl having 1 to 10 C atoms, wherein one or two non-adjacent CH- and / or CH ₂ - groups are N-, O- and / or S- atoms may be replaced / or, of 1-7 H- atoms is optionally replaced by R ^4,

R ⁴ represents F, Cl or OH,

R ⁵ represents H or A '

A ' Represents a non-branched or branched alkyl having 1-6 C atoms, where 1-5 H atoms may be replaced by F,

Hal Represents F, Cl, Br or I,

m Represents 1, 2, 3 or 4,

n Represents 0, 1 or 2,

p Represents 0, 1, 2, 3 or 4].

The present invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereoisomers and hydrates and solvates of the compounds.

Furthermore, the present invention relates to a pharmaceutically acceptable derivative of a compound of formula (I).

The term solvate of the compound is intended to mean an adduct of inert solvent molecules onto the compound formed by the interaction of the compound and the solvent molecule. Solvates are, for example, mono- or dihydrate or alkoxide.

The invention is also understood to relate to solvates of salts.

The term pharmaceutically acceptable derivatives is understood to mean, for example, salts of the compounds according to the invention and also so-called prodrug compounds.

As used herein and unless otherwise indicated, the term "prodrug" refers to a compound that can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) to provide the active compound, Lt; RTI ID = 0.0 > (I) < / RTI > Examples of prodrugs include, but are not limited to, biohydrolyzable amides, biodegradable esters, biodegradable carbamates, biodegradable carbonates, biodegradable ureas, Derivatives and metabolites of compounds of formula (I) which include a bioequivalent moiety such as a water-soluble phosphate analog. In certain embodiments, the prodrug of the compound having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. Carboxylate esters are conveniently formed by esterifying any carboxylic acid moieties present on the molecule. Prodrugs are typically [Burger ' s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh) have.

The expression "effective amount " refers to the amount of a pharmaceutical or pharmaceutically active ingredient that, for example, causes in a tissue, system, animal or human the biological or medical response pursued or required by a researcher or physician.

In addition, the expression "therapeutically effective amount" refers to an amount that has the following results, as compared to a corresponding subject that has not been exposed to this amount:

Ameliorating, curing, preventing or eliminating a disease, syndrome, condition, symptom symptom, disorder or side effect, or also reducing the development of a disease, symptom or disorder.

The expression "therapeutically effective amount" also encompasses an amount effective to increase normal physiological function.

The present invention also relates to a method for the detection of two partial stereoisomers, for example at a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: Lt; RTI ID = 0.0 > (I) < / RTI > which is a mixture of isomers.

This is particularly preferably a mixture of stereoisomeric compounds.

"Tautomeric" means an isomeric form of a compound that is in equilibrium with each other. The concentration of the isomeric form may vary depending on the environment in which the compound is found, for example, depending on whether the compound is a solid or an organic solution or an aqueous solution.

The present invention relates to compounds of formula (I), and salts thereof, and to processes for the preparation of compounds of formula (I), and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof,

Compounds of formula II:

Wherein R, R < ¹ > and R < ³ > have the meanings indicated in claim 1,

With a compound of formula III: < EMI ID =

[Wherein L represents Cl, Br, I or a free or reactive functional modified OH group]

/ RTI > and /

Converting the base or acid of formula (I) into one of its salts.

In the foregoing and below, the radicals R, R < 1 > and R < 3 > have the meanings given in formula (I)

A represents alkyl, which is unbranched (linear) or branched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A is preferably methyl, more preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2- or 3-methylbutyl, - or 2,2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2- or 1-methyl- , 2,2-tri-methylpropyl, further preferably, for example, trifluoromethyl.

A is preferably a non-branched or branched alkyl having 1 to 10 C atoms and the CH ₂ - group can be replaced by an N- and / or O- atom, and 1-7 H atoms can be replaced with R ⁴ .

A is very particularly preferably an alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoro-ethyl.

Furthermore, A preferably represents CH ₂ OCH ₃ , CH ₂ CH ₂ OH or CH ₂ CH ₂ OCH ₃ .

Cyc represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl (preferably unsubstituted or mono-substituted with OH).

A 'represents alkyl, which is unsubstituted (linear or branched) and has 1, 2, 3, 4, 5 or 6 C atoms. A 'is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, Propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, Ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2- or 1,2,2-tri-methylpropyl, furthermore preferably, for example trifluoromethyl.

A 'very particularly preferably represents alkyl having 1, 2, 3, 4, 5 or 6 C atoms, wherein one to three H atoms may be replaced by F.

R ² preferably represents A ', methoxy or hydroxymethyl, particularly preferably H, methyl or trifluoromethyl.

R ³ preferably denotes H, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl or trifluoromethyl, particularly preferably H, methyl or trifluoromethyl.

R ⁵ preferably represents H or methyl.

Ar is preferably selected from o-, m- or p-tolyl, o-, m- or p-ethyl-phenyl, o-, m- or p- o-, m- or p-tert-butyl-phenyl, o-, m- or p-hydroxy- Phenyl, o-, m- or p-methoxy-phenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p- Phenyl, o-, m- or p- (N, N-di-methyl-amino) -phenyl, o-, m- or p- O-, m- or p- (N-ethyl-amino) -phenyl, o-, m- or p- Or o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p- , o-, m- or p-cyano-phenyl, o-, m- or p- (methyl- Phenyl, o-, m- or p-carboxy-phenyl, o-, m- or o-, m- or p-acetylphenyl, o-, m- or p-amino-sulfonylphenyl, o-, m- or p- [2- (morpholine- Yl) ethoxy] -phenyl, o-, m- or p- [3- (N, N- diethyl-amino) -propoxy] -phenyl, , 2,5-, 2,6-, 3,4- or 3,5-di-fluoro-phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 - or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di-bromo-phenyl, 2,4- or Phenyl, 3-amino-4-chloro-phenyl, 2-amino-3-chloro- Amino-4-chloro-2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro- , N-dimethyl-amino-phenyl, 2,3-diamino-phenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4, Dichloro-phenyl, p-iodo-phenyl, 3,6-di-chloro-4-amino- Bromo-phenyl, 3-bromo-6-methoxy-phenyl, 2-fluoro-4-bromo-phenyl, Phenyl, 3-chloro-6-methoxy-phenyl, 3-chloro-4-acetamido- Acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar further preferably represents unsubstituted or mono-, di-, tri-, tetra- or penta substituted phenyl with Hal, A, CN and / or OA.

Regardless of further substitution, Het can be, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3- pyrrolyl, 1-, 3-, 4- or 5-thiazolyl, 2-, 4- or 5-thiazolyl, 3-, Thiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1,2,3-triazole- Yl, 1,2,4-triazol-1, 3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole- Yl, 1,3,4-thiadiazol-2- or-5-yl, 1,2,4-oxadiazol-3- Thiadiazol-4-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3- Indazolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-, or 7-benzo-pyrazolyl, 2-, 4-, Thiazolyl, 2-, 4-, 5-, 6- or 7-benz-isothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, -, 5-, 6-, 7- or 8-iso-quinolyl, 3-, 4-, 5-, 6-, 7- or 8- , 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H- Benzo-dioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol- Benz-oxadiazol-5-yl, azabicyclo- [3.2.1] -octyl or dibenzo-furanyl.

The heterocyclic radical may also be partially or fully hydrogenated.

Regardless of the further substitution, Het is therefore also, for example, 2,3-dihydro-2-, -3-, 4- or -5- furyl, 2,5- Tetrahydro-2- or 3-furyl, 1,3-di-oxolan-4-yl, tetrahydro-2- or 3- -Hydro-l-, -2-, 3-, -4- or -5-pyrrolyl, 2,5-dihydro-l-, Pyrrolidinyl, tetrahydro-1-, 2- or 4-imidazolyl, 2,3-dihydro-1-, 4- or 5-pyrazolyl, tetrahydro-1-, 3- or 4- pyrazolyl, 1,4-dihydro-1-, 2-, 3- or 4- , 2,3,4-tetrahydro-1-, 2-, 3-, -4-, -5- or -6-pyridyl, 1-, 2-, 2-, 3- or 4-morpholinyl, tetrahydro-2-, 3- or -4-pyranyl, 1,4-dioxanyl, Hexahydro-1, 3-or 4-pyridazinyl, hexahydro-1-, 2-, 4- or -5-pyrimidinyl, 1-, 2- Is selected from the group consisting of 3-piperazinyl, 1,2,3,4-tetrahydro-1-, 2-, 3-, -4-, 5-, 6-, , 2-, 3-, 4-, -5-, -6-, -7- or -8-iso-quinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably 2,3-methylene-dioxyphenyl, 3,4- Phenyl, 2,3-ethylenedioxy-phenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoro-methylene-dioxy) -phenyl, 2,3-dihydro- Yl, 2,3- (2-oxo-methylene-dioxy) -phenyl or further 3,4-dihydro-2H-1,5-benzodioxepin- More preferably 2,3-dihydro-benzo-furanyl, 2,3-dihydro-2-oxopuranyl, 3,4-dihydro-2-oxo-1H-quinazolinyl, 2-oxo-2,3-dihydro-benzoxazolyl, 2,3-dihydrobenzimidazolyl, 1,3-dihydroindole, 2-oxo- , 3-dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl .

Het is preferably selected from pyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl , Triazolyl, oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono-or disubstituted with Hal, A, CN and / or OA.

Hal preferably represents F, Cl or Br, but also I, particularly preferably F or Cl.

Throughout the present invention, all radicals present more than once can be the same or different, i.e. they are independent of each other.

The compounds of formula I may have one or more chiral centers and thus may exist in various stereoisomeric forms. Formula I includes all these forms.

Accordingly, the present invention relates to compounds of formula I, especially wherein at least one of said radicals has one of the preferred meanings given above. Some preferred groups of compounds and their pharmaceutically usable salts, and stereoisomers and mixtures thereof in all ratios may be represented by the sub-formulas Ia-Ie, according to formula I, wherein the radicals, I have the meaning indicated in I,

In Ia, R ² represents A ', methoxy or hydroxymethyl;

In Ib, R ³ represents H or A ';

In Ic, Ar Is phenyl unsubstituted or mono-, di-, tri-, tetra- or penta substituted by Hal, A, CN and / or OA,

In Id, Het Is selected from pyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl , Oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono-or disubstituted with Hal, A, CN and / or OA;

In Ie, R represents pyrazol-diyl, imidazol-diyl, isoxazol-diyl or triazol-diyl, each of which is unsubstituted or monosubstituted by R ² ,

R ¹ represents (CH ₂ ) _n Ar, (CH ₂ ) _n Het, A or Cyc,

R ² represents A ', methoxy or hydroxymethyl,

R ³ represents H or A '

Ar represents unsubstituted or phenyl mono-, di-, tri-, tetra- or penta-substituted with Hal, A, CN and / or OA,

Het is selected from pyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, Each of which is unsubstituted or mono- or di-substituted with Hal, A, CN and / or OA,

Cyc represents cyclic alkyl having 3, 4, 5, 6 or 7 C atoms unsubstituted or mono-substituted with OH,

A represents a non-branched or branched alkyl having 1 to 10 C atoms, wherein one or two non-adjacent CH- and / or CH ₂ - groups may be replaced by N-, O- and / or S- And / or 1-7 H atoms may be replaced by R ⁴ ,

R ⁴ represents F, Cl or OH,

A 'represents a non-branched or branched alkyl having 1-6 C atoms, wherein 1-5 H atoms may be replaced by F,

Hal represents F, Cl, Br or I,

n represents 0, 1 or 2;

The compounds of formula I and also the starting materials for the preparation thereof can also be prepared by methods known to those skilled in the art, for example as described in standard methods, for example in Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart As is known in the art, under suitable reaction conditions known for the reaction. Although known per se, variations not mentioned in more detail herein can also be used.

Starting compounds for the preparation of compounds of formula I are generally known. However, if they are novel, they can be prepared in a manner known per se.

The compounds of formula I are preferably obtained by reacting a compound of formula II with a compound of formula III.

In compounds of formula III, L is preferably Cl, Br, I or a free or reactive modified OH group such as an activated ester, imidazolide or alkylsulfonyloxy of 1 to 6 carbon atoms, preferably methyl-sulfonyl Oxy or trifluoromethylsulfonyloxy) or aryl-sulfonyloxy (preferably phenyl- or p-tolylsulfonyloxy) having 6 to 10 carbon atoms.

The reaction is generally carried out in the presence of an acid-coupling agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline.

Addition of alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of weak acids of alkali metals or alkaline earth metals, preferably potassium, sodium, calcium or cesium, may also be preferred.

Preferably, the reaction is carried out in the presence of [dimethylamino- ([1,2,3] triazolo [4,5-b] pyridin-3- yloxy) -methylene] -dimethyl- ammonium hexafluorophosphate [HATU; Coupling reagent] or in the presence of 1-chloro-N, N, 2-trimethyl-1-propenylamine.

Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about -30 to 140, usually from -10 to 90, especially from about 0 to about 70.

Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl-sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of such solvents.

Particularly preferred are acetonitrile, dichloromethane and / or DMF.

Pharmaceutical salts and other forms

The compounds according to the invention may be used in their final non-salt form. The present invention also includes the use of the compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are prepared by most conventional methods. When the compound of formula (I) contains a carboxyl group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base-addition salt. Such bases include, for example, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alkoxides such as potassium ethoxide and sodium propoxide; And various organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of formula I are likewise included. In the case of certain compounds of formula I, acid-addition salts can be prepared by reacting these compounds with pharmaceutically acceptable organic and inorganic acids such as, for example, hydrogen halides such as hydrogen chloride, hydrogen bromide or iodide, other mineral acids and their salts, Such as, for example, sulfates, nitrates or phosphates, and alkyl- and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their salts such as acetate, trifluoroacetate, , Maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like. Thus, pharmaceutically acceptable acid addition salts of compounds of formula I include, but are not limited to, the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (Benzylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentane propionate, digluconate, dihydro (Derived from mucilage acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glutamate, glycerophosphate, glutamate, Hemi-acetylacetonate, heptadate, heptanoate, hexanoate, hydrate, hydrochloride, hydro- Methionine, methane, methane, methanesulfonate, methanesulfonate, methanesulfonate, methanesulfonate, methanesulfonate, methanesulfonate, methanesulfonate, benzenesulfonate, benzenesulfonate, Nitrate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, 2-naphthalenesulfonate, 2-naphthalenesulfonate, Phosphates, phosphonates, phthalates.

Further, the base salts of the compounds according to the present invention include, but are not limited to, aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, , Manganese (II), potassium, sodium and zinc salts. Among the above-mentioned salts, ammonium; Alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium and magnesium are preferred. Salts of the compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include, but are not intended to be limited to, the following salts: primary, secondary and tertiary amines, substituted amines, Amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, But are not limited to, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethanolamine, , tree Ropil amine and tris (hydroxymethyl) methylamine (tromethamine).

Compounds of the present invention containing a basic nitrogen-containing group may be prepared by reacting a (C ₁ -C ₄ ) -alkyl halide such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C ₁ -C ₄₎ alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C ₁₀ -C ₁₈ ) alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; And aryl (C ₁ -C ₄ ) alkyl halides, such as benzyl chloride and phenethyl bromide. Both water-soluble and oil-soluble compounds according to the present invention can be prepared using such salts.

Preferred above-mentioned pharmaceutical salts include, but are not limited to, the following: acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemi-succinate, hydrate, hydrochloride , Hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, Late and tromethamine.

Hydrochlorides, dihydrochlorides, hydrobromides, maleates, mesylates, phosphates, sulfates and succinates are particularly preferred.

Acid-addition salts of the basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid in the usual manner to form the salt. The free base can be regenerated by contacting the salt form with a base in a conventional manner and isolating the free base. The free base form differs somewhat from its corresponding salt form in certain physical properties such as solubility in polar solvents; For purposes of the present invention, the salts otherwise correspond to the respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of the compounds of formula I are formed using metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloropropane, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

Base-addition salts of the acidic compounds according to the invention are prepared by contacting the free acid form in a conventional manner with a sufficient amount of the desired base to form the salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and isolating the free acid. The free acid form differs somewhat from its corresponding salt form in certain physical properties such as solubility in polar solvents; For purposes of the present invention, the salts otherwise correspond to the respective free acid forms thereof.

Where the compound according to the invention contains more than one group capable of forming a pharmaceutically acceptable salt of this type, the invention also includes multiple salts. Exemplary multimeric forms include, but are not limited to, for example, the following: bitartrate, diacetate, difumarate, dimeglumin, diphosphate, disodium and trihydrochloride.

In the context of the foregoing, the expression "pharmaceutically acceptable salt ", as used herein, refers to an active ingredient comprising a compound of formula I in the form of one of its salts, Or to any other salt form of the active ingredient that has been previously used, to give the active ingredient improved pharmacokinetic properties. The pharmaceutically acceptable salt form of the active ingredient may also provide the desired pharmacokinetic properties that were not previously present in the active ingredient for the first time and further provide a positive effect on the pharmacodynamics of the active ingredient Lt; / RTI >

Isotope

Furthermore, the compounds of formula I are intended to include isotopically-labeled forms thereof. The isotopically-labeled forms of the compounds of formula (I) are those in which at least one atom of the compound is replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass of an atom normally found in nature, Is the same as the above-mentioned compound. Examples of isotopes that can be incorporated into compounds of formula I by readily available and well known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H , ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of formula (I), prodrugs thereof or pharmaceutically acceptable salts thereof, containing one or more of the above-mentioned isotopes and / or other isotopes of other elements are intended to be part of the present invention. The isotopically-labeled compounds of formula I can be used in a number of beneficial ways. For example, isotopically-labeled compounds of formula I in which radioactive isotopes such as ³ H or ¹⁴ C are incorporated are suitable for drug and / or substrate tissue distribution assays. These radioisotopes, tritium ( ³ H) and carbon-14 ( ¹⁴ C), are particularly preferred due to their simple preparation and excellent detection capabilities. The incorporation of heavier isotopes such as deuterium ( ² H) into compounds of formula (I) has therapeutic advantages due to the better metabolic stability of such isotopically-labeled compounds. Better metabolic stability translates into increased in vivo half-life or less dosage, which in most cases can represent a preferred embodiment of the present invention. The isotopically-labeled compounds of formula I can be prepared by replacing the normally non-isotopically-labeled reagents with readily available isotopically-labeled reagents to provide the synthesis Can be prepared by carrying out the procedures described in the reaction schemes and the related description.

Deuterium ( ² H) may also be incorporated into the compounds of formula (I) for the purpose of modulating the oxidative metabolism of a compound by primary kinetic isotope effect. The primary dynamical isotope effect is a change in the chemical reaction rate caused by the exchange of isotope nuclei, which is ultimately caused by a change in the ground state energy required for covalent bond formation after the isotope exchange. The exchange of heavier isotopes usually slows down the velocity in the rate-limiting bond failure because it lowers the ground state energy for chemical bonding. If bond breakage occurs at or near the saddle-point region according to the coordinates of the multi-product reaction, the product distribution ratio can be substantially changed. As an explanation: When the deuterium is bonded to a carbon atom at a non-exchangeable position, the speed difference of k _M / k _D = 2-7 is typical. If these rate differences are successfully applied to oxidation-sensitive compounds of formula I, the profile of these compounds in vivo can be dramatically altered, leading to improved pharmacokinetic properties.

In the case of therapeutic agent discovery and development, the skilled artisan strives to optimize the pharmacokinetic parameters while maintaining desirable in vitro properties. A number of compounds with poor pharmacokinetic profiles are considered to be sensitive to oxidative metabolism. Currently available in vivo microsomal assays provide valuable information on this type of oxidative metabolic process which results in the deuterated compounds of formula I with improved stability through resistance to such oxidative metabolism Thereby enabling a rational design of the device. This leads to a significant improvement in the pharmacokinetic profile of the compound of formula I, which results in a significant improvement in vivo half-life (t / 2), maximum therapeutic effect concentration (C _max ), area under the dose response curve (AUC) From the point of view of the increase; And quantitatively in terms of reduced clearance, capacity, and material cost.

The following are intended to be illustrative of the above: Compounds of formula (I) having multiple potential attack sites for oxidative metabolism, such as hydrogen atoms bonded to nitrogen atoms and benzylic hydrogen atoms, Is prepared as a series of analogs replaced by a deuterium atom, some, most, or all of the hydrogen atoms are replaced by deuterium atoms. Half-life measurements enable an advantageous and accurate measurement of the extent to which the improvement in resistance to oxidative metabolism is improved. In this way, it has been confirmed that the half-life of the parent compound can be extended up to 100% as a result of this type of deuterium-hydrogen exchange.

The deuterium-hydrogen exchange in the compounds of formula I can be used to achieve an advantageous alteration of the metabolite spectrum of the starting compound for the reduction or elimination of undesirable toxic metabolites. For example, when toxic metabolites occur through oxidative carbon-hydrogen (CH) bond cleavage, deuterated analogs greatly reduce or eliminate the production of undesired metabolites, even if the particular oxidation is not in the rate determining step Can be reasonably assumed to be able to do so. The most up-to-date additional information in the art about deuterium-hydrogen exchange can be found, for example, in [Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990], [Reider et al., J. Org. Chem. 52, 3326-3334, 1987], [Foster, Adv. Drug Res. 14, 1-40, 1985], [Gillette et al, Biochemistry 33 (10) 2927-2937, 1994] and [Jarman et al. Carcinogenesis 16 (4), 683-688,1993).

The invention further relates to a pharmaceutical composition comprising at least one compound of formula I and / or a pharmaceutically acceptable salt, tautomer and stereoisomer thereof, and mixtures thereof in all ratios, and optionally an excipient and / or adjuvant .

The pharmaceutical formulations may be administered in the form of dosage units containing a predetermined amount of the active ingredient per dosage unit. Such unit may be, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 0.5 mg to 1 mg, according to the condition to be treated, the method of administration and the age, 5 mg to 100 mg, or the pharmaceutical formulation may be administered in the form of a dosage unit containing a predetermined amount of the active ingredient per dosage unit. A preferred dosage unit form is a dosage form comprising the active ingredient in a daily dose or sub-dose, or a corresponding fraction thereof, as indicated above. Further, this type of pharmaceutical formulation may be prepared using methods generally known in the pharmaceutical arts.

The pharmaceutical formulations may be administered by any suitable suitable means, for example, by oral (including buccal or sublingual), rectal, intranasal, topical (including buccal, sublingual or transdermal), intravaginal or parenteral Or in the skin) methods. Such formulations may be prepared, for example, using any method known in the pharmaceutical arts by combining the active ingredient with the excipient (s) or adjuvant (s).

Pharmaceutical formulations suitable for oral administration include, for example, capsules or tablets; Powder or granules; A solution or suspension in an aqueous or non-aqueous liquid; Edible foam or foam foods; Or in an individual unit such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient may be combined with oral, non-toxic and pharmaceutically acceptable inert excipients such as, for example, ethanol, glycerol, water and the like. The powder is prepared by comminuting the compound to a suitable microsized size and mixing it in a similar manner with comminuted pharmaceutical excipients such as starches or edible carbohydrates such as mannitol. Likewise, flavors, preservatives, dispersants and dyes may be present.

Capsules are prepared by preparing a powder mixture as described above and filling it into a molded gelatin shell. Prior to the filling operation, glidants and lubricants, such as highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol, may be added to the powder mixture in solid form. In order to improve the availability of the medicament after capsule administration, a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate may be added.

In addition, if desired or desired, as well as suitable binders, lubricants and disintegrants, dyes may likewise be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubbers such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, Wax and the like. Lubricants used in such dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and disintegrant, and compressing the entire mixture to produce a tablet. The powder mixture may be prepared by mixing the compound ground in a suitable manner with a diluent or base as described above and optionally a binder such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone, a dissolution retarding agent such as paraffin, , And / or an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting it with a binder, such as a syrup, starch paste, acadia mucilage or a solution of cellulose or polymer material, and squeezing through a sieve. As an alternative to granulation, the powder mixture may be passed through a tablet machine to obtain a non-uniform shaped mass and break it down to form granules. Stearic acid, stearate salt, talc, or mineral oil may be added to the granules and lubricated to prevent them from sticking to the tablet casting mold. The lubricated mixture is then pressed to obtain tablets. It is also possible to combine the compounds according to the invention with free-flowing inert excipients, followed by pressing directly without performing granulation or dry-pressing steps to obtain tablets. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a glossy layer of wax may be present. A dye may be added to the coating to enable differentiation between different dosage units.

Oral liquids, such as solutions, syrups and elixirs, may be prepared in dosage unit form so that the provided amount comprises a predetermined amount of the compound. Syrups may be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, and the elixir is prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners may be added as well.

Dosage unit formulations for oral administration may, if desired, be encapsulated in microcapsules. The formulations may also be prepared by coating or inserting, for example, a particulate material with a polymer, wax or the like, in such a manner that the release is extended or delayed.

The compounds of formula I and their pharmaceutically acceptable salts, tautomers and stereoisomers can also be administered in the form of liposome delivery systems, for example in the form of small unilamellar vesicles, large single lamellar vesicles and multilamellar vesicles have. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

The compounds of formula I and their pharmaceutically acceptable salts, tautomers and physiologically functional derivatives can also be delivered using monoclonal antibodies as individual carriers which are coupled to the compound molecules. The compound may also be coupled to a soluble polymer as a targeted pharmaceutical carrier. Such polymers include, but are not limited to, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine substituted with palmitoyl radicals have. The compounds may further comprise a biodegradable polymer class suitable for achieving controlled release of the drug, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyranes, And may be coupled to a cross-linked or amphipathic block copolymer of a polycyanoacrylate and a hydrogel.

A pharmaceutical formulation suitable for transdermal administration may be administered as an independent plaster for prolonged intimate contact with the epidermis of the recipient. Thus, for example, the active ingredient can be delivered from the plasters by iontophoresis, described in general terms in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissues, such as the mouth and the skin, the formulation is preferably applied as a topical ointment or cream. For formulations provided as ointments, the active ingredient may be used with either a paraffinic or a water-miscible cream base. Alternatively, the active ingredient may be formulated to obtain a cream having an oil-in-water cream base or a water-based base.

Pharmaceutical formulations suitable for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations suitable for topical application in the mouth include lozenge, mouthwash and mouthwash.

Pharmaceutical formulations suitable for rectal administration may be administered in the form of a suppository or enema.

Pharmaceutical formulations suitable for intranasal administration wherein the carrier material is solid include coarse powders having a particle size in the range of, for example, 20 to 500 microns, which is in a manner such that a snuff is inhaled, i. E. Is administered by rapid inhalation through the intranasal route from a container containing powder placed close to the nose. Formulations suitable for administration as an intranasal spray or drip-lot with a liquid as the carrier material include water or a solution of the active ingredient in oil.

Pharmaceutical formulations suitable for inhalation administration include particulate powders or mists which may be produced by various types of pressurized dispensers equipped with aerosols, nebulizers or blowers.

Pharmaceutical formulations suitable for vaginal administration may be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, including antioxidants, buffers, bacteriostatics and solutes that render the formulation isotonic with the blood of the recipient to be treated; And aqueous and non-aqueous sterile suspensions which may include suspending media and thickening agents. The formulations can be administered in single or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition, so that a sterile carrier liquid, . Injection solutions and suspensions made according to the recipe can be prepared from sterile powders, granules and tablets.

In addition to the above-mentioned particularly mentioned components, it is to be understood that the formulations may also include other agents customary in the art for certain types of formulations; Thus, for example, formulations suitable for oral administration may include flavoring agents.

The therapeutically effective amount of a compound of formula I will depend on a number of factors including, for example, the age and weight of the animal, the exact condition for which treatment is sought, and the severity thereof, the nature of the formulation and the mode of administration and, ultimately, It is determined by the treatment or treatment veterinarian. However, an effective amount of a compound according to the present invention is generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day, particularly typically 1 to 10 mg / kg body weight per day. Thus, the actual amount per day for adult mammals weighing 70 kg is typically 70 to 700 mg, which is administered as a single dose per day, or as a single daily dose, (E. G., 2, 3, 4, 5 or 6 times) as a series of sub-doses. The effective amount of a salt or solvate or a physiologically functional derivative thereof may be determined as a fraction of an effective amount of the compound per se according to the present invention. A similar dose can be assumed to be appropriate for the treatment of the above-mentioned other conditions.

Combination therapies of this type can be achieved by providing each therapeutic component simultaneously, sequentially or individually. Combination products of this type use compounds according to the invention.

The invention furthermore relates to a medicament comprising at least one compound of formula I and / or a pharmaceutically acceptable salt, tautomer and stereoisomer thereof, and mixtures thereof in all ratios, and at least one additional pharmaceutical active ingredient.

The invention also relates to a kit (kit) consisting of the following individual packs:

(a) an effective amount of a compound of formula I and / or a pharmaceutically usable salt, tautomer and stereoisomer thereof, and mixtures thereof in all ratios, and

(b) An effective amount of an additional pharmaceutical active ingredient.

The set includes a suitable container, such as a box, individual bottle, bag or ampoule. The set may comprise, for example, an effective amount of each of an effective amount of a compound of formula I and / or a pharmaceutically acceptable salt, solvate and stereoisomer and mixtures thereof in all ratios, and an effective amount of a dissolved or lyophilized form of addition And may contain individual ampoules containing a pharmaceutically active ingredient.

As used herein, the term "treating" is intended to include alleviating, partially or totally alleviating the symptoms associated with a disorder or disease, or slowing or stopping further progress or worsening of the symptoms, Quot; means preventing or preventing the disease or disorder in an individual.

The term "effective amount " associated with a compound of formula (I) refers to an amount of an effective amount of a compound of formula (I) that alleviates, partially or totally alleviates the symptoms associated with the disorder or disease, or slows or abolishes further progression or worsening of the symptoms, May refer to an amount capable of preventing or preventing the disease or disorder in an individual having or at risk of developing an inflammatory condition, an immunological condition, a cancer or metabolic condition.

In one embodiment, an effective amount of a compound of formula (I) is an amount that inhibits intracellular PDHK, e.g., ex vivo or in vivo. In some embodiments, an effective amount of a compound of formula (I) is selected from the group consisting of 10%, 20%, 30%, 40%, 50%, 60% or more of intracellular PDHK, , 70%, 80%, 90% or 99%. For example, an effective amount of a compound of formula (I) in a pharmaceutical composition may be at a level that can achieve the desired effect: for example, for both oral and parenteral administration, About 0.005 mg / kg of body weight to about 10 mg / kg of body weight.

Usage

The present invention relates to compounds of formula I, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures thereof in all ratios, for use in the treatment of cancer, diabetes and cardiac ischemia in particular.

Furthermore, the present invention provides a compound of formula I for use in the treatment of insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, heart failure, cardiomyopathy, myocardial ischemia, hyperlipidemia, mitochondrial disease, mitochondrial myopathy Compounds, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures of all ratios thereof.

The present invention relates to a method for the treatment or prevention of cancer, diabetes and cardiac ischemia, comprising administering to a subject in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof, .

Also provided are compounds of formula I and / or pharmaceutically acceptable salts, tautomers and stereoisomers thereof for the manufacture of a medicament for the treatment or prevention of PDHK-induced diseases or PDHK-induced pathologies in mammals Which is a use in a method of administering a therapeutically effective amount of a compound according to the present invention to a diseased mammal in need of such treatment. The amount of treatment will depend on the particular disease, which can be determined by one skilled in the art without great difficulty.

The expression "PDHK-inducible disease or condition" refers to a pathological condition dependent on PDHK activity. Diseases associated with PDHK activity include cancer, diabetes, and cardiac ischemia.

The present invention particularly relates to the use of a compound of formula I and its pharmaceutically acceptable salts, tautomers and stereoisomers, and all ratios thereof, for use in the treatment of diseases in which the inhibition, regulation and / ≪ / RTI >

The present invention particularly relates to compounds of formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures thereof in all ratios, for use in the inhibition of PDHK.

Representative cancers useful for treating or preventing a compound of formula I include, but are not limited to, the following: hair, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, thoracic, Cancer of the bladder, uterus, cervix, breast, ovary, testes or other reproductive organs, skin, thyroid, blood, lymph node, kidney, liver, pancreas, brain, central nervous system, solid tumors and hematologic tumors.

Moreover, typical cancers useful for treating or preventing a compound of formula I include but are not limited to brain cancer (glioma), glioblastoma, leukemia, Bannayan-Zonana syndrome, Cowden disease, Inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ventriculomegaly, lymphedema, colon, head and neck, kidney, lung, liver, kidney, Melanoma, ovary, pancreas, prostate, sarcoma, osteosarcoma, giant cell tumors of bone and cancer of the thyroid gland.

Preferably, the invention relates to a method wherein the disease is cancer.

Particularly preferably, the invention relates to a method wherein the disease is cancer and which is administered sequentially, sequentially or alternatively, simultaneously with the administration of one or more other active agents.

The compounds of formula I disclosed above may be administered in combination with other known therapeutic agents including anticancer agents. As used herein, the term " anti-cancer agent "refers to any agent that is administered to a patient suffering from cancer for the treatment of cancer.

The chemotherapeutic treatment as defined above may be applied as a sole therapy or may include, in addition to the compounds of formula (I) disclosed herein, conventional surgery or radiotherapy or pharmacotherapy. Such pharmacologic therapies, such as chemotherapy or targeted therapies, may include one or more, preferably one, of the following antineoplastic agents:

Alkylating agent

Such as, for example, altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, But are not limited to, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, , Nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone;

But are not limited to, apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-302 ⁴ , VAL-083 ⁴ ;

Platinum compound

For example, carboplatin, cisplatin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picofelate, Picoplatin, satraplatin;

Lobaplatin, nedaplatin, picoplatin, satraplatin; < RTI ID = 0.0 >

DNA modifier

For example, amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine;

Amsacrine, brostallicin, pixantrone, laromustine ^1,3 ;

Topoisomerase inhibitor

For example, etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan;

Amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule modifier

For example, the compounds of the present invention may be used in combination with other drugs such as carbazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, Vindesine, vinflunine;

Fosbretabulin, tesetaxel;

Antimetabolite

For example, asparaginase ³ , azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, a drug selected from the group consisting of enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, femetrecine, Pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur;

But are not limited to, doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur ^2,3 , trimetrexate;

Anticancer antibiotic

For example, bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C ( mitomycin C), romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plicamycin;

Aclarubicin, peplomycin, pirarubicin;

Hormone / antagonist

For example, there may be mentioned, for example, abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, the compounds of the present invention include dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, But are not limited to, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, tryptorelin, diethylstilbestrol );

Acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide ^1,3 ; < RTI ID = 0.0 >

Aromatase inhibitor

For example, aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone;

Formestane;

Small molecule kinase inhibitor

Such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, legorapenib (see, for example, regulafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, evil, Axitinib;

But are not limited to, those selected from the group consisting of afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, Orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, tiotropinib, ), Trametinib, pimasertib, brivanib alaninate, cediranib, apatinib ⁴ , cabozantinib S- -malate) ^1,3, eve Ruti nip (ibrutinib) ^1,3, Ikoma tinip (icotinib) ^4, unit sold ten (buparlisib) ^2, Shifa tinip (cipatinib) ^4, Kobe Tinip (cobimetinib) ^1,3, Ide Raleigh ten (idelalisib) ^1,3, Pedra tinip ^{(fedratinib) 1, XL-647} 4;

Photosensitizer

For example, methoxsalen ³ ;

Porfimer sodium, talaporfin, temoporfin;

Antibody

Such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, omeprazole, The compounds of the present invention may be used in combination with other medicaments such as ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab ^2,3 ;

But are not limited to, catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, The compounds of the present invention are useful in the treatment of obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, Zalutumumab, zanolimumab, matuzumab, dalotuzumab ¹ , ² , ³ , onartuzumab ¹ , ³ , racotumomab ¹ , Tabalumab ^1,3 , EMD-525797 ⁴ , nivolumab ^1,3 ;

Cytokine

For example, aldesleukin, interferon alfa ² , interferon alpha 2a ³ , interferon alpha 2b ^2,3 ;

Celmoleukin, tasonermin, teceleukin, oprelvekin ^1,3 , recombinant interferon beta-1a ⁴ ;

Drug conjugate

For example, denileukin diftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estraconazole, Estramustine, gemtuzumab, ozogamicin, < RTI ID = 0.0 >aflibercept; < / RTI >

Cortredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, and the like. Technetium (99mTc) arctitumomab (technetium (99mTc) arcitumomab) ^1,3 , vintafolide ^1,3 ;

vaccine

For example, sipuleucel ³ ; Vitespen ³ , emepepimut-S ³ , oncoVAX ⁴ , rindopepimut ³ , troVax ⁴ , MGN-1601 ⁴ , MGN-1703 ⁴ ;

etc

But are not limited to, alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lenalidomide, The compounds of the present invention can be used in combination with one or more of the following compounds: lentinan, metirosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel ³ , sizofiran Tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat, and the like;

But are not limited to, celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, ), Lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, lidamole, But are not limited to, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, Valspodar, gendicine ⁴ , picibanil ⁴ , reolysin ⁴ , retaspimycin hydrochloride ^1,3 , trebinanipine, trebananib ^2,3 , virulizin ⁴ , carfilzom (carfilzom) ib) ^1,3 , endostatin ⁴ , immucothel ⁴ , belinostat ³ , MGN-1703 ⁴ ;

¹ Prop. INN (P roposed I nternational N onproprietary N ame): Proposed International Nonproprietary Name

² Rec. INN (R ecommended I nternational N onproprietary N ames): the recommended International Nonproprietary Name

³ USAN ( U nited S tates A doped N ame)

⁴ no INN. : No common name

The following abbreviations each have the following definitions:

aq (Aqueous), h (hour), g (Grams), L (liter), mg (milligrams), MHz (Megahertz), min. (Minutes), mm (millimeters), mmol (millimoles), mM (Millimolar concentration), mp (melting point), eq (equivalent), mL (milliliter), μL (Microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl ₃ (deuterated chloroform), CD ₃ OD (deuterated methanol), CH ₃ CN (acetonitrile), c-hex (cyclohexane), DCC (Diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), DMSO (dimethylformamide), and the like, in the presence of a base such as dicyclohexylcarbodiimide, dicyclohexylcarbodiimide, -d ₆ (deuterated dimethylsulfoxide), EDC (1- (3- dimethyl-amino-propyl) -3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et ₂ O ( Diethyl ether), EtOH (ethanol), HATU (dimethylamino- ([1,2,3] triazolo [4,5- b] pyridin- 3- yloxy) methylene] dimethylammonium hexafluorophosphate), HPLC (High performance liquid chromatography), i-PrOH (2-propanol), K ₂ CO ₃ (potassium carbonate), LC (Methanol), MgSO ₄ (magnesium sulfate), MS (mass spectrometer), MTBE (methyl tert-butyl ether), NaHCO ₃ (sodium hydrogencarbonate), NaBH ₄ (sodium borohydride), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (Retention time), SPE (solid phase extraction), TBTU (2- (1-H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate), TEA Ethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), UV (ultraviolet).

Explanation of in vitro test

Explanation of in vitro test

Abbreviation:

GST = glutathione-S-transferase

FRET = fluorescence resonance energy transfer

HTRF? = (Homogenous time resolved fluorescence)

HEPES = 4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid buffer

DTT = dithiothreitol

BSA = bovine serum albumin

CHAPS = 3 - [(3-Colamidopropyl) dimethylammonio] -1-propanesulfonate

Biochemical Activation Test of PDHK2: PDC Inactivation Assay

Biochemical activity assays for PDHK2 are based on inactivation of PDC through phosphorylation by PDHK2. This assay is carried out in two steps: a PDHK2 reaction in which the isolated PDC is phosphorylated by PDHK2 with ATP as an auxiliary substrate, and a PDC activity assay in which the pyruvate and NAD are converted to acetyl-CoA and NADH. PDC activity is associated with an increase in NADH, and therefore, directly detectable (Exc 340nm, Em 450nm) by increasing the fluorescence signal. Inhibition of PDHK2 leads to a lower phosphorylation state and consequently a lessening of PDC activity and a stronger increase of the NADH fluorescence signal.

PDC inactivation assays are performed on Greiner 384-well microtiter plates and used for high throughput screens. (10 dilution concentration) and PDC (isolated from porcine heart, Sigma-Aldrich, 20 mU / ml final concentration) were mixed with 4 μl of PDHK2 (human, rec, Carna Bioscience, 10 ng / of kinase buffer (15 mM potassium phosphate buffer for 30 min at room temperature and the absence or presence, pH 7.0, 60 mM KCl, 1.5 mM DTT, 2.5 mM MgCl 2, 0.0125% (w / v) BSA, 0.125% Pluronic F-68 ). ≪ / RTI > The kinase reaction is initiated by the addition of 4 μl ATP substrate solution (fc 5 μM, kinase buffer). After incubation at 37 캜 for 30 minutes, 40 의 of PDC reaction solution (100 mM Tris / HCl, pH 7.8, 0.5 mM EDTA, 1 mM MgCl ₂ , 50 mM NaF, 0.25 mM Coenzyme A, 5 mM pyruvate, 1 mM NAD, 5 mM DTT, 1 mM thiamine pyrophosphate). The first fluorescence measurement is performed on a Perkin Elmer Envision (Exc 340 nm, Em 450 nm). The reaction is incubated at room temperature for 45 minutes. Thereafter, the second fluorescence measurement is performed, and the PDC activity is calculated as the difference between the two measurements. For the PDHK2 assay, use the inhibitor-free PDHK2 response. The pharmacokinetic 0 value used is DCA (Sigma-Aldrich) at a final concentration of 3 mM. The inhibition value (IC50) was measured using GeneData's program Symyx Assay Explorer® or Condosseo®.

Isothermal titration calorimeter

ITC measurements were performed on a VP-ITC micro calorimeter (Microcal, LLC / GE Healthcare Bio-Sciences AB, Uppsala, Sweden). In general, the titration was carried out by titrating the protein (50 [mu] M) into the test compound (5 [mu] M) of 12 [mu] l of injection. All binding experiments were carried out at 30 < 0 > C. Generally, the test compound was a diluted form of DMSO stock solutions into the assay buffer with the highest final concentration of 1% DMSO. Measuring buffer was 20mM HEPES, 135mM KCl, 1mM TCEP , 2mM MgCl 2, 15mM NaH 2 PO 4, pH 7.5. Human PDHK2 (12-407) was prepared in E. coli as his-tagged protein and purified by affinity chromatography. The tag was removed by side specific protein hydrolysis. Prior to titration, the protein buffer was changed to a measuring buffer containing the same DMSO concentrate as the test compound dilution. ITC data analysis was performed using the same supplier's Origin 7 calorimeter software. For most measurements, a binding model of one binding site was estimated. According to the applied mathematical model, it is possible to calculate the stoichiometry (N) as well as the binding constant (K _A ), observed binding enthalpy ( ^{ΔH obs} ) of the complex formed. Prior to the analysis, raw data was estimated from the saturation value at the appropriate end and corrected for the dilution column. Protein concentrations were calibrated with reference to well-behaved standard inhibitors titrated to allow direct comparison between each series of experiments and protein preparations. Apparent stoichiometry values define the fraction of binding competent protein and compensate for relative error in protein concentration measurements. These calibrated protein concentrations were used to establish a series of ITC experiments using test compounds. The random deviations from the ideal 1: 1 stoichiometry observed here were due to errors in the chemical concentration. This intention compound concentration was also calibrated to achieve a 1: 1 stoichiometry in fit.

Cell assay for measuring compound activity

Compound activity was measured in a cell immunofluorescence assay. Human HEK293T cells were seeded in clear, black 384-well plates on the bottom and grown overnight.

The next day, the test compound was added to the wells, and the plate was incubated for 5 hours. The cells were then fixed with formaldehyde, permeabilized and blocked. Primary antibody, Anti-PDH-E1alpha (pSer300), AP1064 (Merck Millipore) was added and incubated overnight in plate wells. Cells were then washed and secondary antibody, Alexa Fluor 488, goat anti-rabbit ab (A-11008, Invitrogen) was added with Hoechst 33258 (H3569, Invitrogen) and incubated in the plate well for 1 hour. Finally, the cells were washed and the plates were measured on a laser scanning cytometer acumen hci (TTpLabtech).

The original data was normalized to the pharmacokinetic inhibitor control and the dose response curve was generated by plotting the% effect value using the software package Genedata screener (Genedata).

In the above and below, all temperatures are expressed in ° C. In the following examples, "normal work-up" means that: if required, water is added and, if desired, the pH is adjusted to between 2 and 10 depending on the composition of the final product, The mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulphate, evaporated and the residue is purified by chromatography on silica gel and / or crystallization.

LC / MS:

HPLC-Method P:

Gradient: 3.3 min; Flow rate: 2.4 ml / min, 4% B from 0 min, 2.8 min 100% B, 3.3 min 100% B

A: water + HCOOH (0.05% Vol.); B: Acetonitrile + HCOOH (0.04% Vol.)

Column: Chromolith SpeedROD RP 18e 50-4.6

Wavelength: 220 nm

Agilent devices

LC / MS:

HPLC-Method S:

Gradient: Flow rate: 2 ml / min, 5% B from 0 min, 8.1 min 100% B, 8.5 min 5% B, 10 min 5% B

A: water + TFA (0.1% Vol.); B: Acetonitrile + TFA (0.1% Vol.)

Column: XBridge C8, 3.5 mm, 4.6 x 50 mm

Wavelength: 220 nm

¹ H NMR was recorded on a Bruker DPX-300, DRX-400, AVII-400 or BRUKER 500 MHz spectrometer using the residual signal of the deuterated solvent as an internal standard. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (DMSO-d ₆ , δ = 2.49 ppm in ¹ H NMR). ¹ H NMR data were recorded as follows: chemical shift (multiplicity, coupling constant and HF). The multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Example

Pyrazolyl-piperidine derivatives:

Example 1

Methyl-1- [4- (2-p-tolyl-2H-pyrazol-3-yl) -piperidin- 1 (R) -3,3,3- trifluoro-2- -Yl] -propan-1-one ("A1")

1.1 4 - ((E) -3-Dimethylamino-acryloyl) -piperidine-l-carboxylic acid tert-butyl ester

Carboxylic acid tert-butyl ester (4.0 g, 17.6 mmol) was dissolved in N, N-dimethylformamide dimethylacetal (50 mL) and heated to reflux Temperature). The mixture was stirred at reflux for 64 hours. The mixture was cooled to ambient temperature and evaporated under reduced pressure. This product was used in the next step without further purification; Yield: 4.7 g (84%) yellow crystals; Rt: 1.85 min;

¹ H NMR (400 MHz, CDCl ₃ ):? [Ppm] 7.64-7.54 (d, J = 12.5 Hz, 1H), 5.10-5.00 (d, J = 12.5 Hz, 1H), 4.21-4.02 ), 3.12-2.69 (m, 8H), 2.43-2.34 (m, 1H), 1.87-1.71 (m, 2H), 1.67-1.47 (m, 2H), 1.46-1.45 (s, 9H).

1.2 4- (2-p-Tolyl-2H-pyrazol-3-yl) -piperidine- 1 -carboxylic acid tert-butyl ester

Carboxylic acid tert-butyl ester (0.5 g; 1.77 mmol) and p-tolylhydrazine hydrochloride (280.9 mg; 1.77 mmol) were added to a solution of 4 - ((E) -3- dimethylamino- acryloyl) -piperidine- ) Was dissolved in absolute ethanol (40 mL) and heated to reflux. The mixture was stirred at reflux for 3 hours and evaporated under reduced pressure. The residue was applied to flash chromatography (Isco CombiFlash®Rf, column: Interchim PuriFlash®PF-50SIHP-JP / 55G) using petroleum ether / ethyl acetate. Yield: 352 mg (46%), brown gum ); Rt: 2.53 min.

1.3 4- (2-p-Tolyl-2H-pyrazol-3-yl) -piperidine hydrochloride

Butyl ester (352.0 mg; 0.814 mmol) was dissolved in absolute ethanol (4 mL) and the solution was stirred at room temperature for 2 hours. And hydrochloric acid (25%; 2 mL) was added. The mixture was stirred at 25 < 0 > C for 3 h, at 50 < 0 > C for 3 h and evaporated under reduced pressure. The mixture was applied to RP-Flash-chromatography (Isco Companion (R), column: Interchim puriFlash®IR-50C18 / 55G). Hydrochloric acid (25%) (2 mL) was added to the pure fractions and lyophilized; Yield: 127 mg (56%), off-white solid; Rt: 1.11 min; ¹ H NMR (400 MHz, DMSO-d ₆ ):? [Ppm] 8.34 (s, 1H), 7.55 (d, J = 1.8 Hz, (Dt, J = 12.5, 3.1 Hz, 2H), 2.88 (tt, J = 11.7, 3.7 Hz, 1H), 2.64 , 3H), 1.80-1.72 (m, 2H), 1.67-1.52 (m, 2H).

1.4 Methyl-1- [4- (2-p-tolyl-2H-pyrazol-3-yl) -piperidin- 1 (R) -3,3,3- trifluoro-2- -Yl] -propan-1-one ("A1")

(122.0 mg; 0.439 mmol) and (R) -3,3,3-trifluoro-2-hydroxypiperidine hydrochloride -2-methyl-propionic acid (76.4 mg, 0.483 mmol) was dissolved in DMF (1.0 mL) and the mixture was cooled in an ice bath. [Dimethylamino- ([1,2,3] triazolo [4,5-b] pyridin-3-yloxy) -methylene] -dimethyl-ammonium hexafluorophosphate [HATU; Coupling reagent] (200.4 mg; 0.527 mmol) followed by N-ethyldiisopropylamine (0.187 mL; 1.1 mmol) was added, the cooling was removed and the mixture was stirred at 25 <0> C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 81 mg (48%), white amorphous solid; (Purity: 100%, Rt: 2.11 min, [M + H] &lt; + &gt;382);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.54 (d, J = 1.8 Hz, 1H), 7.34 (s, 4H), 7.05 (s, 1H), 6.34 - 6.27 (m, 1H) (M, 2H), 1.64-1.36 (m, 2H), 2.39 (s, 3H) 5H).

The following compounds were prepared as described for Example 1 ("A1"):

(R) -3,3,3-trifluoro-2-hydroxy-l- {4- [2- (4- methoxy- phenyl) -2H- pyrazol- 3- yl] -piperidin- Yl} -2-methyl-propan-1-one ("A2 &

(243.0 mg, 0.736 mmol) and (R) -3,3,3-trifluoro-4-methoxy-phenyl) -2H-pyrazol-3-yl] -piperidine dihydrochloride 2-hydroxy-2-methyl-propionic acid (127.9 mg, 0.809 mmol) was dissolved in DMF (2 mL) and the mixture was cooled in an ice bath. HATU (335.7 mg; 0.883 mmol) followed by N-ethyldiisopropylamine (0.5 mL; 2.943 mmol) was added, cooling was removed and the mixture was stirred at 25 <0> C for 4 h. The mixture was purified by RP-flash-chromatography (Isco Companion (R)); Column: Interchim puriFlash®IR-50C18 / 205G), and the pure fraction was lyophilized; Yield: 230 mg (79%), light yellow solid; (Purity: 100%, Rt: 2.01 min, [M + H] &lt; + &gt;398); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.54 (d, J = 1.8 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.16 - 6.91 (m, 3H), 6.30 (s, 2H), 2.67-2.52 (m, 1H), 1.87-1.71 (m, 2H), 4.72 (s, , 1.65-1.37 (m, 5H).

2- {5- [1 - ((R) -3,3,3-Trifluoro-2-hydroxy-2- methyl- propionyl) -piperidin- Yl} benzonitrile ("A3")

(102.2 mg, 0.354 mmol) and (R) -3,3,3-trifluoro-2-hydroxy-2-hydroxy- Hydroxy-2-methyl-propionic acid (67.2 mg; 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 7 mg (5%), amorphous colorless solid; (Purity: 100%, Rt: 2.03 min, [M + H] &lt; + &gt; ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.73 (d, J = 4.5 Hz, 1H), 8.30 - 8.22 (m, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.70 1H), 7.62 (m, 1H), 7.45 (d, J = 4.6 Hz, 1H), 7.35-7.27 , 2H), 4.15-4.00 (m, 1H), 3.41-3.11 (m, 1H), 3.08-2.83 (m, 1H), 2.37-2.19 (m, 2H), 1.58 (s, 3H).

(R) -3,3,3-trifluoro-1- {4- [2- (2-fluoro-phenyl) -2H-pyrazol- 3- yl] -piperidin- 2-hydroxy-2-methyl-propan-1-one (&

(99.7 mg; 0.354 mmol) and (R) -3,3,3-trifluoro-pyridine hydrochloride 2-methyl-propionic acid (67.2 mg; 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 10 mg (7%) beige amorphous solid; (Purity: 100%, Rt: 1.99 min, [M + H] &lt; + &gt; ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.66 - 7.57 (m, 2H), 7.57 - 7.51 (m, 1H), 7.51 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H ), 7.00 (s, IH), 6.34 (s, IH), 4.89-4.21 (m, 2H), 3.09-2.7 ), 1.83-1.64 (m, 2H), 1.64-1.34 (m, 5H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- (2- -Yl] -propan-1-one ("A5")

(98.3 mg; 0.354 mmol) and (R) -3,3,3-trifluoro-2-hydroxypiperidine hydrochloride Methyl-propionic acid (67.2 mg; 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) followed by N-ethyldiisopropyl-amine (0,15 mL; 0.885 mmol) was added, cooling was removed and the mixture was stirred at 25 <0> C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 18 mg (13%) beige amorphous solid; (Purity: 100%, Rt: 2.07 min, [M + H] &lt; + &gt; ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.57 (d, J = 1.8 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.39 - 7.32 (m, 1H), 7.32 - 7.27 ( 2H), 2.98-2.75 (m, 1H), 2.64-2.40 (m, 2H), 6.99 (d, J = , 1.92 (s, 3H), 1.79-1.62 (m, 2H), 1.58-1.36 (m, 5H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- (2- -Yl] -propan-1-one ("A6")

(98.3 mg; 0.354 mmol) and (R) -3,3,3-trifluoro-2-hydroxypiperidine hydrochloride Methyl-propionic acid (67.2 mg, 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 17 mg (13%) beige amorphous solid; (Purity: 100%, Rt: 2.12 min, [M + H] + 382);

^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 7.55 (d, J = 1.8 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.32 - 7.22 (m, 3H), 7.01 (s, 3H), 1.87-1.71 (s, 1H), 6.31 (s, 1H), 4.84-4.28 (m, 2H), 3.06-2.81 (m, 2H), 1.68-1.39 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-1- {4- [2- (2-methoxy- phenyl) -2H-pyrazol- 3- yl] -piperidin- Yl} -2-methyl-propan-1-one ("A7 &

(104.0 mg, 0.354 mmol) and (R) -3,3,3-trifluoro-benzoic acid methyl ester were added to a solution of 4- [2- (2-methoxy- -2-hydroxy-2-methyl-propionic acid (67.2 mg, 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 6 mg (4%) beige amorphous solid; (Purity: 100%, Rt: 1.96 min, [M + H] + 398).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl) -piperidin-4-yl] Yl} benzonitrile ("A8")

(102.2 mg, 0.354 mmol) and (R) -3,3,3-trifluoro-2-hydroxy-2-hydroxy- Hydroxy-2-methyl-propionic acid (67.2 mg; 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 9 mg (6%) beige amorphous solid; (Purity: 100%, Rt: 1.99 min, [M + H] + 393).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl) -piperidin-4-yl] Yl} benzonitrile ("A9")

(102.2 mg; 0.354 mmol) and (R) -3,3,3-trifluoro-2-hydroxy-benzyl chloride Hydroxy-2-methyl-propionic acid (67.2 mg; 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 6 mg (4%) beige amorphous solid; (Purity: 100%, Rt: 2.01 min, [M + H] + 393).

(R) -3,3,3-Trifluoro-1- {4- [2- (3-fluoro- phenyl) -2H-pyrazol- 3- yl] -piperidin- 2-methyl-propan-1-one ("A10")

(99.7 mg; 0.354 mmol) and (R) -3,3,3-trifluoro-pyridine hydrochloride -2-hydroxy-2-methyl-propionic acid (67.2 mg; 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 14 mg (10%) beige amorphous solid; (Purity: 100%, Rt: 2.08 min, [M + H] &lt; + &gt; ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.64 - 7.54 (m, 2H), 7.43 - 7.30 (m, 3H), 7.01 (s, 1H), 6.35 (s, 1H), 4.86 - 4.28 (m, 2H), 3.16-2.37 (m, 3H), 1.89-1.72 (m, 2H), 1.64-1.38 (m, 5H).

(2-chloro-phenyl) -2H-pyrazol-3-yl] -Hydroxy-2-methyl-propan-1-one ("A11 &

(105.6 mg, 0.354 mmol) and (R) -3,3,3-trifluoro-pyridin-2-yl- 2-Hydroxy-2-methyl-propionic acid (67.2 mg; 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 48 mg (34%) beige amorphous solid; (Purity: 100%, Rt: 2.06 min, [M + H] + 402-404); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.74 - 7.68 (m, 1H), 7.63 - 7.53 (m, 4H), 7.00 (s, 1H), 6.36 - 6.29 (m, 1H), 2H), 1.78-1.66 (m, 2H), 1.62-1.38 (m, 5H).

(R) -1- {4- [2- (3-chloro-phenyl) -2H-pyrazol-3- yl] -piperidin- 1 -yl} -3,3,3-trifluoro- Methyl-propan-1-one ("A12")

(105.6 mg; 0.354 mmol) and (R) -3,3,3-trifluoro-benzenesulfonyl chloride were added to a solution of 4- [2- (3-chloro-phenyl) 2-Hydroxy-2-methyl-propionic acid (67.2 mg; 0.425 mmol) was dissolved in DMF (1 mL) and the mixture was cooled in an ice bath. HATU (201.9 mg; 0.531 mmol) and subsequently N-ethyldiisopropylamine (0,15 mL; 0.885 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 32 mg (22%) as a pale yellow oil; (Purity: 100%, Rt: 2.18 min, [M + H] + 402-404); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.62 - 7.53 (m, 4H), 7.50 - 7.44 (m, 1H), 7.10 - 6.89 (m, 1H), 6.37 - 6.33 (m, 1H ), 4.83-4.28 (m, 2H), 3.08-2.94 (m, 2H), 2.73-2.51 (m, 1H), 1.87-1.73 (m, 2H), 1.62-1.38 (m, 5H).

(4-chloro-phenyl) -2H-pyrazol-3-yl] -piperidin- -Hydroxy-2-methyl-propan-1-one ("A13 &

(92.0 mg, 0.351 mmol) and 1- [1 - ((R) -3,3,3-tetrahydro-2H-pyrazol- (66.7 mg; 0.422 mmol) was dissolved in DMF (1 mL) at 0 &lt; 0 &gt; C And the mixture was cooled in an ice bath. HATU (200.5 mg; 0.527 mmol) followed by N-ethyldiisopropylamine (0,15 mL; 0.879 mmol) was added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 55 mg (39%) pale beige solid; (Purity: 100%, Rt: 2.13 min, [M + H] + 402-404);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.62 - 7.57 (m, 3H), 7.54 - 7.49 (m, 2H), 7.01 (s, 1H), 6.37 - 6.32 (m, 1H), 2H), 3.06-2.90 (m, 2H), 2.70-2.51 (m, 1H), 1.86-1.72 (m, 2H), 1.59-1.40 (m, 5H).

(4-fluoro-phenyl) -2H-pyrazol-3-yl] -piperidin- 1 -yl} - Hydroxy-2-methyl-propan-1-one ("A14 &

(94.0 mg, 0.383 mmol) and 1- [1 - ((R) -3,3,3-trifluoro-phenyl) -2H- 4-yl] -cyclopropanecarboxylic acid ethyl ester (72.7 mg, 0.460 mmol) was dissolved in DMF (1 mL) and treated with &lt; RTI ID = 0.0 & , And the mixture was cooled in an ice bath. HATU (218.6 mg; 0.575 mmol) followed by N-ethyl-diisopropylamine (0.16 mL; 0.958 mmol) was added, cooling was removed and the mixture was stirred at 25 <0> C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 74 mg (50%); (Purity: 100%, Rt: 2.03 min, [M + H] &lt; + &gt;

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.56 (d, J = 1.8 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.42 - 7.33 (m, 2H), 7.01 (s, (M, 2H), 1.64-1.75 (m, 2H), 3.06-2.86 (m, 2H) 1.34 (m, 5 H).

(3-chloro-2-fluoro-phenyl) -2H-pyrazol-3-yl] Trifluoro-2-hydroxy-2-methyl-propan-1-one (&

(85.0 mg, 0.304 mmol) and (R) -3,3,3-tri (4-chloro-phenyl) -2H-pyrazol- Hydroxy-2-methyl-propionic acid (57.6 mg; 0.365 mmol) was dissolved in DMF (2 mL) and the mixture was cooled in an ice bath. HATU (173.3 mg; 0.456 mmol) followed by N-ethyldiisopropyl-amine (0.13 mL; 0.760 mmol) was added, cooling was removed and the mixture was stirred at 25 <0> C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 75 mg (59%) as a pale yellow solid; (Purity: 100%, Rt: 2.07 min, [M + H] + 420-422); ^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 7.83 - 7.78 (m, 1H), 7.65 (d, J = 1.8, 1H), 7.59 - 7.53 (m, 1H), 7.42 (td, J 2H), 3.09-2.83 (m, IH), 2.79-2.67 (m, IH), 7.09 (s, 2.66 - 2.41 (m, 1H), 1.79-1.69 (m, 2H), 1.63-1.40 (m, 5H).

(R) -3,3,3-Trifluoro-1- {4- [2- (2-fluoro-4-methyl- phenyl) -2H-pyrazol-3-yl] -piperidin- Methyl} -propan-1-one ("A16")

(80.0 mg, 0.308 mmol) and (R) -3,3,3-tri (2-fluoro-4-methyl- Fluoro-2-hydroxy-2-methyl-propionic acid (58.5 mg; 0.370 mmol) was dissolved in DMF (2 mL) and the mixture was cooled in an ice bath. HATU (176 mg; 0.463 mmol) followed by N-ethyldiisopropyl-amine (0.13 mL; 0.771 mmol) was added, cooling was removed and the mixture was stirred at 25 <0> C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 48 mg (39%) as a pale yellow solid; (Purity: 100%, Rt: 2.09 min, [M + H] + 400); ^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 7.59 (d, J = 1.8 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.21 (M, 1H), 2.61 (m, 1H), 2.61 (m, 2H) - 2.48 (m, 1H), 2.42 (s, 3H), 1.78-1.65 (m, 2H), 1.64-1.34 (m, 5H).

(R) -1- [4- (2-tert-butyl-2H-pyrazol-3- yl) -piperidin- 1 -yl] -3,3,3-trifluoro- Methyl-propan-1-one ("A17")

(107.0 mg, 0.359 mmol) and (R) -3,3,3-trifluoro-2-hydroxy-2-hydroxy- Hydroxy-2-methyl-propionic acid (115.7 mg; 0.717 mmol) was dissolved in DMF (3 mL). The yellow solution was cooled with stirring in a water-ice-bath. N-ethyldiisopropylamine (0.90 mL; 5.292 mmol) and HATU (299.9 mg; 0.789 mmol) were added. The ice-bath was removed and the yellow solution was stirred at room temperature for 14 hours. The solution was cooled in an ice-bath. (57.8 mg; 0.359 mmol), N-ethyldiisopropylamine (0.06 ml; 0.359 mmol) and HATU (204.5 mg; 0.538 mmol). After 15 minutes, the ice bath was removed. The solution was stirred at room temperature for another 90 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered by suction and evaporated to dryness. The residue was purified by preparative HPLC (Agilent®, column: SunFire ™ Prep C18 OBD ™ 5 μM; 30 x 150 mm). The pure fraction was lyophilized; Yield: 81 mg (65%), colorless solid; (Purity 100%, Rt: 1.93 min, [M + H] &lt; + &gt;348);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.22 (d, J = 1.8 Hz, 1H), 7.19 - 6.86 (m, 1H), 6.14 (s, 1H), 4.95 - 4.34 (m, 2H), 3.40-3.28 (m, 1H), 3.23-2.63 (m, 2H), 1.92-1.75 (m, 2H), 1.64-1.42 (m, 14H).

(R) -1- {4- [2- (2-Chloro-4-trifluoromethyl-phenyl) -2H-pyrazol- 3- yl] -piperidin- 3-trifluoro-2-hydroxy-2-methyl-propan-1-one (&

(110.0 mg, 0.334 mmol) and (R) -3,3,3-trifluoro-phenyl) -2H-pyrazol- 2-methyl-propionic acid (63.3 mg; 0.400 mmol) was dissolved in DMF (2 mL) and the mixture was cooled in an ice bath. HATU (190.3 mg; 0.500 mmol) and N-ethyldiisopropyl-amine (0.14 mL; 0.834 mmol) were added, cooling was removed and the mixture was stirred at 25 [deg.] C for 20 h. The mixture was purified directly by preparative HPLC (Agilent (R), column: Chromolith®prep 100-25). The pure fraction was lyophilized; Yield: 34 mg (22%) as a pale yellow solid; (Purity 100%, Rt: 2.29 min, [M + H] + 470-472); ^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 8.19 (d, J = 1.3 Hz, 1H), 7.93 (dd, J = 8.2, 1.3 Hz, 1H), 7.82 (d, J = 8.2 Hz 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.01 (s, IH), 6.38 (s, IH), 4.80-4.25 (m, 2H), 3.05-2.85 2.50 (m, 2H), 1.81-1.66 (m, 2H), 1.60-1.40 (m, 5H).

(R) -1- {4- [2- (5-bromo-pyrimidin-2-yl) -2H-pyrazol- 3- yl] -piperidin- 1 -yl} -3,3,3 2-hydroxy-2-methyl-propan-1-one ("A19 &

19.1 2-yl) -2H-pyrazol-3-yl] -piperidine-l-carboxylic acid tert-butyl ester

Carboxylic acid tert-butyl ester (102.0 mg; 0.361 mmol) and 5-bromo-2-hydrazinopyrimidine (prepared as described in Example 1) 136.6 mg; 0.722 mmol) was suspended in diethylene glycol dimethyl ether (4.0 mL). The yellow suspension was heated in a microwave oven at 200 &lt; 0 &gt; C for 65 min. The suspension was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered off with suction and evaporated to dryness. The residue was purified by RP-chromatography; Yield: 62 mg (42%) yellow oil.

19.2 Bromo-2- (5-piperidin-4-yl-pyrazol-l-yl) -pyrimidine dihydrochloride

Preparation as described for "A32" (step 32.3)

19.3 (R) -1- {4- [2- (5-bromo-pyrimidin-2-yl) -2H-pyrazol- 3- yl] -piperidin- 1 -yl} -3,3,3 -Trifluoro-2-hydroxy-2-methyl-propan-1-one

Pyrimidine dihydrochloride (57.3 mg, 0.150 mmol) and (R) -3,3,3-tri (4-fluoro- Fluoro-2-hydroxy-2-methyl-propionic acid (47.4 mg; 0.300 mmol) was dissolved in DMF (3 mL). N-Ethyldiisopropylamine (0.90 mL; 5.292 mmol) followed by HATU (125.3 mg; 0.330 mmol) was added with stirring. The suspension was stirred overnight at room temperature. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered by suction and evaporated to dryness. The oily residue was purified by preparative HPLC (Agilent®, column: SunFire ™ Prep C18 OBD ™ 5 μM; 30 x 150 mm). The pure fraction was lyophilized; Yield: 24 mg (36%) as a colorless solid; (Purity 100%, Rt: 1.91 min, [M + H] + 448-451);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 9.09 (s, 2H), 7.71 (d, J = 1.7 Hz, 1H), 7.07 (s, 1H), 6.48 - 6.40 (m, 1H) (M, 2H), 4.96-4.32 (m, 2H), 3.67 (tt, J = 11.7, 3.5 Hz, 1H), 3.18-2.57 .

(R) -3,3,3-trifluoro-2-hydroxy-1- (4- {2- [4- (1 -hydroxy- Yl) -2-methyl-propan-1-one ("A20 &

2-ol hydrochloride (92.7 mg, 0.288 mmol) and (R) -3,3-dihydro-2H-pyrazol- 3-Trifluoro-2-hydroxy-2-methyl-propionic acid (92.9 mg; 0.576 mmol) was dissolved in DMF (5 mL) and the mixture was cooled in an ice bath. N-Ethyldiisopropylamine (0.35 mL; 2.016 mmol) followed by HATU (245.8 mg; 0.633 mmol) was added, cooling was removed and the mixture was stirred at room temperature for 14 hours. The solution was diluted with water, made basic by adding saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered by suction and evaporated to dryness. The residue was purified by chromatography; Yield: 28.5 mg (23%), colorless solid; (Purity 100%, Rt: 1.86 min, [M + H] &lt; + &gt;426); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.65 - 7.58 (m, 2H), 7.55 (d, J = 1.8 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.02 (s, 2H), 2.66-2.50 (m, 1H), 1.89-1.74 (m, 2H), 3.06-2.88 (m, 2H), 1.62-1.39 (m, 11H).

(4-tert-butyl-phenyl) -2H-pyrazol-3-yl] Hydroxy-2-methyl-propan-1-one ("A21 &

(58.4 mg; 0.351 mmol) and HATU (147.6 mg; 0.380 mmol) were dissolved in DMF (1 mL) and treated with &lt; RTI ID = 0.0 & , And the mixture was stirred at room temperature for 1 hour. This solution was added to a solution of 4- [2- (4-tert-butyl-phenyl) -2H-pyrazol-3-yl] -piperidine hydrochloride (93.7 mg, 0.293 mmol) and N-ethyldiisopropylamine ml; 0.732 mmol) (dissolved in DMF (1 mL)). The mixture was stirred at room temperature for 14 hours. (58.4 mg, 0.351 mmol), HATU (147.6 mg; 0.380 mmol) and N-ethyldiisopropylamine (0.13 mmol) were added to a solution of (R) -3,3,3-trifluoro- mL; 0.732 mmol) was dissolved in DMF (1 mL), stirred for 1 hour, and added to the reaction mixture. The reaction mixture was stirred for 2 hours at room temperature and then treated with (R) -3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (58.4 mg; 0.351 mmol), HATU mmol) and N-ethyldiisopropylamine (0.13 mL; 0.732 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 2 hours, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash RF 200); Yield: 82 mg (64%) Colorless solid; (Purity 97%, Rt: 2.34 min, [M + H] &lt; + &gt;424); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.59 - 7.51 (m, 3H), 7.42 - 7.35 (m, 2H), 7.04 (s, 1H), 6.32 (s, 1H), 4.84 - 2H), 1.63-1.41 (m, 2H), 3.07-2.89 (m, 2H), 2.65-2.49 (m, 1H), 1.91-1.73 (m, 2H), 1.63-1.41 (m,

The following compounds were prepared as described for example "A21 ".

(R) -3,3,3-Trifluoro-2-hydroxy-1- {4- [2- (4-isopropyl- phenyl) -2H-pyrazol-3- yl] -piperidin- Yl} -2-methyl-propan-1-one ("A22 &

Yield: 87 mg (45%) colorless solid; (Purity 96%, Rt: 2.36 min, [M + H] &lt; + &gt;410); ¹ H NMR (400 MHz, DMSO-d ₆ )? [Ppm] 7.55 (d, J = 1.8 Hz, 1H), 7.43-7.44 (m, 4H), 7.03 (s, 2H), 1.50-1.45 (m, 5H), 1.26 (d, 2H), 4.81-4.31 (m, 2H), 3.05-2.90 J = 6.9 Hz, 6H).

(4-chloro-2-fluoro-phenyl) -2H-pyrazol-3-yl] -piperidin- Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A23"

Yield: 45 mg (15%) as a colorless solid; (Purity 94%, Rt: 2.20 min, [M + H] + 420-422); ^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 7.76 (dd, J = 9.9, 2.3 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.62 - 7.57 (m, 1H) 2H), 3.04-2.89 (m, 1H), 2.75-2.67 (m, 1H), 7.51-7.46 (m, , 2.62-2.49 (m, 1H), 1.79-1.68 (m, 2H), 1.59-1.42 (m, 5H).

(R) -1- {4- [2- (4-ethyl-phenyl) -2H-pyrazol-3- yl] -piperidin- 1 -yl} -3,3,3-trifluoro- -Hydroxy-2-methyl-propan-1-one ("A24 &

Yield: 56.5 mg (32%) as a colorless solid; (Purity 97%, Rt: 2.26 min, [M + H] &lt; + &gt;396); ¹ H NMR (400 MHz, DMSO-d ₆ )? [Ppm] 7.55 (d, J = 1.8 Hz, 1H), 7.40-7.33 (m, 4H), 7.02 (M, 2H), 1.62 (m, 2H), 4.80-4.32 (m, 2H), 3.05-2.89 - 1.36 (m, 5H), 1.24 (t, J = 7.6 Hz, 3H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- ] -Propan-1-one ("A25")

Yield: 67 mg (27%) as a colorless solid; (Purity 97%, Rt: 2.00 min, [M + H] &lt; + &gt;368); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.59 - 7.52 (m, 3H), 7.51 - 7.44 (m, 3H), 7.04 (s, 1H), 6.33 (s, 1H), 4.83 - 2H), 1.61-1.39 (m, 2H), 4.26 (m, 2H), 3.05-2.88 (m, 2H), 2.62-2.52 (m, 1H), 1.79 (t,

(R) -1- {4- [2- (2,4-difluoro-phenyl) -2H-pyrazol-3- yl] -piperidin- 1 -yl} -3,3,3-tri Fluoro-2-hydroxy-2-methyl-propan-1-one (&

Yield: 60 mg (35%) colorless solid; (Purity 97%, Rt: 2.06 min, [M + H] + 404); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.67 - 7.53 (m, 3H), 7.33 - 7.25 (m, 1H), 7.04 (s, 1H), 6.35 (s, 1H), 4.81 - 2H), 1.59-1.39 (m, 2H), 3.07-2.86 (m, 1H), 2.73-2.62 (m, ).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- {4- [2- (4- trifluoromethyl- phenyl) -2H- ] -Piperidin-1-yl} -propan-1-one ("A27"

To a solution of (R) -3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (90.3 mg; 0.571 mmol) in dichloromethane (0.5 mL) (76.3 mg, 0.571 mmol), and the solution was stirred at room temperature for 1.5 hours. This solution was slowly added to a solution of 4- [2- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -piperidine (129.8 mg; 0.439 mmol) and triethylamine (44.5 mg; ) In dichloromethane (0.5 ml), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash RF 200); Yield: 40 mg (21%) as a colorless solid; (Purity 100%, Rt: 2.29 min, [M + H] &lt; + &gt; ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.97 - 7.89 (m, 2H), 7.80 - 7.73 (m, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.06 (s, 1H), 6.43 (s, 1H), 4.84-4.34 (m, 2H), 3.17-2.90 (m, 2H), 2.68-2.51 m, 5H).

(R) -3,3,3-Trifluoro-1- {4- [2- (2-fluoro-4-methoxy- phenyl) -2H-pyrazol- 3- yl] -piperidin- Yl} -2-hydroxy-2-methyl-propan-1-one (&

For example, as described for "A27 ".

Yield: 70 mg (56%) colorless solid; (Purity 100%, Rt: 2.06 min, [M + H] + 416); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.57 (d, J = 1.9 Hz, 1H), 7.43 (t, J = 8.9 Hz, 1H), 7.09 (dd, J = 12.1, 2.7 Hz 1H), 7.02 (s, 1H), 6.95-6.90 (m, 1H), 6.36-6.44 (m, 1H), 4.88-4.21 1H), 2.71-2.60 (m, 1H), 2.59-2.44 (m, 1H), 1.82-1.65 (m, 2H), 1.63-1.33 (m, 5H).

(R) -1- {4- [1- (5-chloro-pyridin-2-yl) -lH- pyrazol-3- yl] -piperidin- 1 -yl} -3,3,3-tri Fluoro-2-hydroxy-2-methyl-propan-1-one (&

29.1 4- (2H-Pyrazol-3-yl) -piperidine-l-carboxylic acid tert-butyl ester

Butyl ester (220.0 mg; 0.779 mmol) was dissolved in ethanol (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours. Hydrazinium hydroxide (42 L, 0.857 mmol) and triethylamine (120 L, 0.857 mmol) were added and the solution was stirred at reflux for 2 hours. Another portion of hydrazinium hydroxide (42 μl; 0.857 mmol) was added and the yellow solution was refluxed for 1 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum; Yield: 164 mg (84%) beige oil; (Rt: 1.91 min, (M + H-t-butyl 196.1).

29.2 Pyrazol-3-yl] -piperidine-l-carboxylic acid tert-butyl ester

To a solution of 4- (2H-pyrazol-3-yl) -piperidine-l-carboxylic acid tert-butyl ester (80.0 mg; 0.318 mmol) in DMF (2.0 mL) was added potassium carbonate (263.9 mg; mmol) were added. 2,5-Dichloro-pyridine (56.5 mg; 0.382 mmol) was slowly added over a period of 15 minutes, and the reaction mixture was stirred overnight at 110 ° C. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum; Yield: 30 mg (26%) Beige solid.

29.3 4- [l- (5-Chloro-pyridin-2-yl) -lH-pyrazol-3-yl] -piperidine dihydrochloride

For example, as described for "A32" (step 32.3)

29.4 (R) -1- {4- [2- (5-chloro-pyridin-2-yl) -2H-pyrazol- 3- yl] -piperidin- 1 -yl} -3,3,3-tri Fluoro-2-hydroxy-2-methyl-propan-1-one

Step 29.4 was prepared as described in example "Al ".

Purified by preparative HPLC (Agilent®, column: SunFire ™ Prep C18 OBD ™ 5 μM; 30 x 150 mm). The pure fraction was lyophilized; Yield: 13 mg (41%), colorless solid; (Purity 100%, Rt: 1.93 min, [M + H] + 403-405); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.53 - 8.45 (m, 2H), 8.06 (dd, J = 8.8, 2.6 Hz, 1H), 7.91 - 7.85 (m, 1H), 7.07 ( (m, 2H), 3.28-3.09 (m, 1H), 3.06-2.95 (m, 1H), 2.91-2.73 (m, 1H), 2.04-1.92 (m, 2H), 1.75-1.56 (m, 2H), 1.54 (s, 3H).

rac-3,3,3-Trifluoro-l- {4- [2- (2-fluoro-4- methoxy- phenyl) -2H-pyrazol- 3- yl] -piperidin- Yl} -2-hydroxy-2-methyl-propan-1-one ("A30"

"A30" was prepared as described for example "A1 ".

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 89 mg (27%) as a colorless solid; (Purity 100%, Rt: 2.05 min, [M + H] + 416);

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.57 (d, J = 1.9 Hz, 1 H), 7.43 (t, J = 8.9 Hz, , 7.02 (s, 1H), 6.95-6.90 (m, 1H), 6.36-6.44 (m, 1H), 4.88-4.21 , 2.71-2.60 (m, 1H), 2.59-2.44 (m, 1H), 1.82-1.65 (m, 2H), 1.63-1.33 (m, 5H).

Example 31

(R) -1- {4- [2- (2,4-Difluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidin- , 3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A31"), synthesis of diastereomeric mixtures

31.1 1- (3-Methyl-pyridin-4-yl) -ethanone

A solution of methylmagnesium chloride (3.0 M in THF, 18.4 mL; 55.058 mmol) in THF (200 mL) was slowly added to a solution of N-methoxy-3, N-dimethyl- isonicotinamide (7,63 g; 42.352 mmol) It was added under N ₂ atmosphere to a stirred solution of from 0 ℃, and the mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with 40 mL of saturated aqueous NH ₄ Cl-solution under ice-cooling. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The oil phase residue was purified by flash chromatography (CombiFlash RF 200. Yield: 5.29 g (92%) colorless solid; (purity 100%, Rt: 0.92 min).

31.2 (E) -3-dimethylamino-l- (3-methyl-pyridin-4-yl)

(1.10 g; 8.138 mmol) was dissolved in N, N-dimethylformamide dimethylacetal (4.0 mL) in a microwave vessel, and a solution of 14 Lt; / RTI &gt; The reaction mixture was evaporated to dryness and the residue (1.64 g) was used in the next step without further purification.

31.3 3-yl] -3-methyl-pyridine &lt; / RTI &gt;

(244.8 mg, 1.287 mmol) and 2,4-difluorophenylhydrazine hydrochloride (232 mg, 1.287 mmol) were added to a solution of (3-dimethylamino- mmol) were dissolved in ethanol (5.0 mL) and refluxed for 2 hours. The mixture was evaporated to dryness and the residue was purified by flash chromatography (CombiFlashRF 200); Yield: 130 mg (37%) orange oil; (Purity 100%, Rt: 1.55 min, (M + H) 272.1).

31.4 4- [2- (2,4-Difluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidine hydrochloride

3-yl) -3-methyl-pyridine (130.0 mg, 0.479 mmol) was dissolved in ethanol (2 mL). Hydrochloric acid solution (1 M, 0.96 mL; 0.958 mmol) was added and the mixture was hydrogenated with platinum oxide hydrate at 5 bar and 50 &lt; 0 &gt; C for 14 h. The reaction mixture was filtered and concentrated in vacuo; Yield: 138 mg (92%) as a beige solid;

31.5 (R) -1- {4- [2- (2,4-Difluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidin- , 3-trifluoro-2-hydroxy-2-methyl-propan-1-

Manufacture as described for "A27 "; Yield: 82 mg (44%) as a colorless solid; Mixtures of diastereomers; (Purity 98%, Rt: 2.13 min, (M + H) 418.2).

Pyrazol-3-yl] -3-methyl-piperidine-l- {(3R, 4R) -4- [2- (2,4-difluoro- Methyl-propan-1-one ("A32")

And (R) -1 - {(3S, 4S) -4- [2- (2,4-difluoro-phenyl) -2H-pyrazol- Yl} -3,3,3-trifluoro-2-hydroxy-2-methyl-propan-

의 합성

Synthesis of

32 / 33.1 3-yl] -3-methyl-piperidine-l-carboxylic acid terf-butyl ester

4- [2- (2,4-Difluoro-phenyl) -2H- pyrazol-3-yl] -3-methyl-piperidine hydrochloride (357,00 mg; 1.138 mmol) and NaHCO ₃ (286.7 di-tert-butyl dicarbonate (248.3 mg; 1.138 mmol) dissolved in dioxane (8.0 mL) was added to a solution of Lt; / RTI &gt; The reaction mixture was diluted with water and saturated aqueous NaHCO ₃ - solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash RF 200); Yield: 305 mg (71%) colorless oil; Mixtures of diastereomers; (Purity 100%, Rt: 2.51 min, (M + H) 378.2).

32 / 33.2 (3R, 4R) -4- [2- (2,4-Difluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidine- 1- carboxylic acid tert- 3-yl] -3-methyl-piperidine-l-carboxylic acid tert-butyl ester was prepared in accordance with the general method of example 1 from l- (3S, 4S) -4- [2- (2,4- difluoro- ester

The diastereoisomers were separated by chiral chromatography (column: Chiralpak AD-H, solvent: CO ₂ + 5% MeOH).

Yield (32.2): 79.8 mg (26%) colorless oil; HPLC (Chiralpak AD-H; CO ₂ / MeOH-95/5): Rt 2.08 min;

Yield (33.2): 75 mg (25%) colorless oil; HPLC (Chiralpak AD-H; CO ₂ / MeOH-95/5): Rt 2.37 min.

32.3 (3R, 4R) -4- [2- (2,4-Difluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidine hydrochloride

A solution of hydrogen chloride (4.0 M, 3.0 mL in dioxane) was added to a solution of

(3R, 4R) -4- [2- (2,4-Difluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidine- 1- carboxylic acid tert- (79.0 mg; 0.209 mmol) and stirred overnight at ambient temperature. The reaction was concentrated in vacuo. The residue was used without further purification in the next step.

32.4 Pyrazol-3-yl] -3-methyl-piperidine-l- {(3R, 4R) -4- [2- (2,4-difluoro- Yl} -3,3,3-trifluoro-2-hydroxy-2-methyl-propan-

3-yl] -3-methyl-piperidine hydrochloride (65.6 mg; 0.209 mmol) was added to a solution of (3R, 4R) -4- [2- (2,4- difluoro-phenyl) (42.9 mg; 0.272 mmol) and HATU (119.2 mg; 0.314 mmol) were added to DMF (8.0 mL, ). N-ethyldiisopropylamine (243.1 mg; 1.881 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was purified by RP-flash chromatography (CombiFlashRF 200); Yield: 86 mg (99%) colorless solid; (Purity 100%, Rt: 2.1 min, (M + H) 418.2); HPLC (Chiralpak AD-H; CO ₂ / MeOH-95/5): Rt 3.84 min; ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.64 - 7.59 (m, 1H), 7.59 - 7.50 (m, 1H), 7.49 - 7.41 (m, 1H), 7.27 - 7.19 (m, 1H ), 6.79-6.72 (m, 1H), 6.35-6.27 (m, 1H), 4.67-4.33 (m, 1H), 4.08-4.00 (m, 2H), 1.99-1.84 (m, 1H), 1.76-1.63 (m, 2H), 1.61-1.43 (m, 3H), 0.66-0.59 (m, 3H).

33.3 (3S, 4S) -4- [2- (2,4-Difluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidine hydrochloride

For example, as described for "A32" (step 32.3)

33.4 (4-fluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidine-l- Yl} -3,3,3-trifluoro-2-hydroxy-2-methyl-propan-

Preparation and purification as described for example "A32" (step 32.4); Yield: 73 mg (88%) as a colorless solid; (Purity 100%, Rt: 2.1 min, (M + H) 418.2); HPLC (Chiralpak AD-H; CO ₂ / MeOH-95/5): Rt 4.65 min; ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.64 - 7.59 (m, 1H), 7.59 - 7.52 (m, 1H), 7.51 - 7.40 (m, 1H), 7.28 - 7.19 (m, 1H 1H), 6.76 (s, 1H), 6.34-6.66 (m, 1H), 4.60-4.32 , 2H), 1.96-1.83 (m, 1H), 1.77-1.61 (m, 2H), 1.57-1.49 (m, 3H), 0.67-0.56 (m, 3H).

Example 34

(4-chloro-phenyl) -5-methyl-1H-pyrazol-3-yl] -piperidin- Fluoro-2-hydroxy-2-methyl-propan-1-one ("A34"

34.1 4- (5-methyl-2H-pyrazol-3-yl) -pyridine

(4-pyridinyl) -1,3-butanedione (815.0 mg; 4.995 mmol) was suspended in ethanol (6.0 mL), hydrazinium hydroxide (242.8 L, 4.995 mmol) Was stirred at 85 &lt; 0 &gt; C for 48 hours. The reaction mixture was diluted with saturated NaHCO ₃ - solution (pH 7-8) and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum; Yield: 703 mg (88%) Beige solid.

34.2 4- (5-methyl-2H-pyrazol-3-yl) -piperidine hydrochloride

4- (5-methyl-2H-pyrazol-3-yl) -piperidine hydrochloride (689.0 mg; 4.328 mmol) was dissolved in ethanol (10 mL). Hydrochloric acid solution (1 M, 8.7 mL; 8.656 mmol) was added and the mixture was hydrogenated with platinum oxide hydrate (80% Pt, 100.0 mg) at atmospheric pressure and at room temperature for 14 hours. The reaction mixture was filtered and concentrated in vacuo; Yield: 873 mg (100%). Yellow solid.

34.3 4- (5-methyl-2H-pyrazol-3-yl) -piperidine-l-carboxylic acid tert-butyl ester

4- (5-methyl-2H-pyrazol-3-yl) -piperidine hydrochloride (827.9 mg; 4.105 mmol) was dissolved in water (14.0 mL). _{NaHCO 3 (1.03 g; 12.315 mmol} ) and di -tert- butyl dicarbonate; was added (dissolved in dioxane (26.0 mL)) (895.9 mg 4.105 mmol) , and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (CombiFlash RF 200); Yield: 1.013 g (93%) as a colorless solid; Rt: 1.88 min, (M + Ht-butyl) 210.2).

34.4 5-methyl-1H-pyrazol-3-yl] -piperidine-l-carboxylic acid tert-butyl ester

Carboxylic acid tert-butyl ester (247.6 mg, 0.933 mmol), 4-chlorophenylboronic acid (291.8 mg; 1.866 mmol) and 2- ), Anhydrous copper acetate (254.2 mg; 1.399 mmol) and a small amount of molecular sieve 4 Å in dichloromethane (8.0 mL). Pyridine (147.6 mg; 1.866 mmol) was added and the mixture was stirred overnight at ambient temperature. The reaction mixture was evaporated to dryness and the residue was purified by RP-chromatography (CombiFlash RF 200); Yield: 318 mg (91%) yellow oil; R t: 2.79 min, (M + H) 376.2-378.2.

34.5 4- [l- (4-Chloro-phenyl) -5-methyl-lH-pyrazol-3- yl] -piperidine hydrochloride

(4.0 M, dioxane; 4.0 mL) was added to a solution of 4- [2- (4-chloro-phenyl) -5-methyl-2H-pyrazol- Carboxylic acid tert-butyl ester (318.4 mg; 0.847 mmol) and stirred at ambient temperature for 14 hours. The reaction was concentrated in vacuo; Yield: 264 mg (100%).

34.6 (4-chloro-phenyl) -5-methyl-1H-pyrazol-3-yl] -piperidin- Fluoro-2-hydroxy-2-methyl-propan-1-one ("A34"

The acylation reaction was carried out as described in example "A27 ".

Purification by RP-flash chromatography (CombiFlash RF 200).

Yield: 62 mg (46%) as a colorless solid; (Purity 100%, Rt: 2.38 min, (M + H) 416.1-418.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ 7.64 - 7.56 (m, 4H), 7.08 (s, 1H), 6.23 (s, 1H), 4.94 - 4.28 (m, 2H), 3.31 - 3.02 (m (M, 2H), 2.37 (s, 3H), 2.06-1.92 (m, 2H), 1.79-1.46 (m, 5H).

Example 35

(4-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl] -piperidin- 3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A35"

35.1 4- (5-Trifluoromethyl-2H-pyrazol-3-yl) -piperidine hydrochloride

Pyrazol-3-yl) -pyridine (619.0 mg; 2.904 mmol) was dissolved in ethanol (10 mL). Hydrochloric acid solution (1 M, 5.8 mL; 5.808 mmol) was added and the mixture was hydrogenated overnight at room temperature under atmospheric pressure with platinum oxide hydrate (80% Pt, 100.0 mg). The reaction mixture was filtered and concentrated in vacuo; Yield: 817 mg (100%) pale yellow solid.

35.2 4- (5-Trifluoromethyl-2H-pyrazol-3-yl) -piperidine- 1 -carboxylic acid tert-butyl ester

(752.0 mg; 2.940 mmol) was dissolved in water (14.0 mL). The reaction mixture was stirred at room temperature for 2 hours. Dissolving NaHCO ₃ (741.0 mg; 8.820 mmol) and di-tert-butyl dicarbonate (641.6 mg; 2.940 mmol) in dioxane (26.0 mL) was added and the mixture was stirred at room temperature for 14 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (CombiFlash RF 200); Yield: 806 mg (86%) colorless solid; (Purity 100%, Rt: 2.33 min, (M + Ht-butyl) 264.1).

35.3 5-Trifluoromethyl-2H-pyrazol-3-yl] -piperidine-l-carboxylic acid tert-butyl ester

Carboxylic acid tert-butyl ester (260.0 mg, 0.814 mmol), 4-chlorophenylboronic acid (254.6 mg, ; 1.628 mmol), anhydrous copper acetate (221.8 mg; 1.221 mmol) and a small amount of molecular sieve 4 Å in dichloromethane (8.0 mL). Pyridine (128.8 mg; 1.628 mmol) was added and the reaction was stirred at ambient temperature for 48 hours. The reaction mixture was evaporated to dryness and the residue was purified by RP-chromatography (CombiFlash RF 200); Yield: 333 mg (95%) colorless oil; Rt: 2.90 min, (M + H) &lt; / RTI &gt; 430.2-432.1.

35.4 4- [2- (4-Chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl] -piperidine hydrochloride

Example &lt; RTI ID = 0.0 &gt; A34 &lt; / RTI &gt; (step 34.5)

35.5 (4-chloro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl] -piperidin- 3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A35"

The acylation reaction was carried out as described for Example 27. [

Purification by RP-flash chromatography (CombiFlash RF 200); Yield: 56 mg (37%) as a colorless solid; (Purity 100%, Rt: 2.54 min, (M + H) 470.1-472.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.69 - 7.63 (m, 2H), 7.63 - 7.58 (m, 2H), 7.05 - 6.96 (m, 1H), 6.95 - 6.81 (m, 1H ), 4.89-4.25 (m, 2H), 3.03-2.89 (m, 2H), 2.59 (s, 1H), 1.90-1.73 (m, 2H), 1.71-1.41 (m, 5H).

(R) -1- [4- (2-isopropyl-2H-pyrazol-3- yl) -piperidin- 1 -yl] -3,3,3-trifluoro-2- Methyl-propan-1-one ("A36")

Preparation and purification as described in example "A17 &quot;; Yield: 186 mg (9%), brown solid; (Purity 96%, Rt: 2.99 min); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.32 (d, J = 1.6 Hz, 1H), 7.07 (s, 1H), 5.98 (s, 1H), 4.80-4.78 (m, 1H) (M, 1H), 4.60-4.54 (m, 1H), 4.47-4.40 (m, 1H), 3.14-3.12 m, 2H), 1.55-1.45 (m, 5H), 1.36 (d, J = 6.48 Hz, 6H).

(R) -1- [4- (2-cyclohexyl-2H-pyrazol-3- yl) -piperidin- 1 -yl] -3,3,3-trifluoro-2- Methyl-propan-1-one ("A37")

Preparation and purification as described for example "A17 "; yield: 142 mg (9%), pale yellow solid; (Purity 99%, Rt: 3.92 min);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.30 (d, J = 1.7 Hz, 1H), 7.07 (s, 1H), 5.98 (s, 1H), 4.81-4.79 (m, 1H) , 4.46-4.44 (m, IH), 4.16-4.10 (m, IH), 3.12-3.10 (m, IH), 3.06-3.03 m, 10H), 1.52 (s, 3H), 1.48 - 1.39 (m, 3H), 1.22 - 1.16 (m, 1H).

(R) -1- [4- (2-benzyl-2H-pyrazol-3- yl) -piperidin- 1 -yl] -3,3,3- trifluoro-2- Methyl-propan-1-one ("A38")

Preparation and purification as described for example "A17 &quot;; Yield: 7 mg (1%), (purity 95.7%, Rt: 5.36 min); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.52 (d, J = 1.7 Hz, 1H), 7.35-7.27 (m, 3H), 7.05 (d, J = 6.9 Hz, 2H), 6.10 (d, J = 1.8 Hz, IH), 5.38 (s, 2H), 5.31-5.29 (m, IH), 4.44-4.42 (m, 2H), 2.89-2.78 , 2H), 1.63-1.60 (m, 3H), 1.59-1.50 (m, 2H).

(4-fluoro-phenyl) -2H-pyrazol-3-yl] -piperidin- 1 -yl} -3,3,3- Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A39 &

Preparation as described for Example 1; Yield: 187 mg (29%), (purity 99.1%, Rt: 4.18 min); ^{1 H NMR (400 MHz, DMSO} -d 6): δ [ppm] 7.76-7.73 (m, 1H), 7.67-7.63 (m, 1H), 7.60 (s, 1H), 7.44-7.40 (m, 1H) , 7.04 (s, IH), 6.33 (br s, IH), 4.68-4.65 (m, IH), 4.35-4.33 (m, IH), 2.95-2.93 ), 1.73-1.71 (m, 2H), 1.49-1.35 (m, 5H).

(4-fluoro-phenyl) -5-methyl-1H-pyrazol-3-yl] -piperidin- Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A40 &

.

.

(4-fluoro-phenyl) -5-methyl-2H-pyrazol-3-yl] -piperidin- Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A41 &

Examples "A40" and "A41" were prepared as described for example "A34 ".

Purification by RP-flash chromatography (CombiFlash RF 200). Separation by preparative HPLC (Agilent (R), column: ChromolithSpeedROD RP18e 50-4.6) of the obtained regioisomer; Example "A40", Yield: 33 mg (19%) colorless solid; (Purity 100%, Rt: 2.23 min, (M + H) 400.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.56 - 7.49 (m, 2H), 7.37 - 7.28 (m, 2H), 7.01 (s, 1H), 6.14 (s, 1H), 4.81 - (M, 2H), 3.23-3.66 (m, 1H), 2.93-2.70 (m, 2H), 2.28 (s, 3H), 1.99-1.86 (m, 2H), 1.69-1.43 (m, 5H);

Example "A41", Yield: 12 mg (7%) colorless solid; (Purity 100%, Rt: 2.09 min, (M + H) 400.1); ¹ H NMR (400 MHz, DMSO-d ₆ )? [Ppm] 7.52-7.44 (m, 2H), 7.39-7.30 (m, 2H), 7.03 (s, 2H), 1.63-1.32 (m, 5H), 4.23 (m, 2H), 3.04-2.80 (m, 2H), 2.65-2.46 (m,

(R) -1- {4- [2- (4-fluoro-phenyl) -5-trifluoromethyl-2H-pyrazol-3-yl] -piperidin- , 3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A42"

Example "A42" was prepared as described for example "A35 ".

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 71 mg (50%) colorless solid; (Purity 100%, Rt: 2.43 min, (M + H) 454.1); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.66 - 7.58 (m, 2H), 7.47 - 7.39 (m, 2H), 7.07 - 6.95 (m, 1H), 6.93 - 6.77 (m, 1H ), 2.70-2.52 (m, 1H), 4.88-4.25 (m, 2H), 3.07-2.84 (m, 2H), 1.90-1.72 (m, 2H), 1.69-1.40 (m, 5H).

(R) -1- [4- (2-phenyl-5-trifluoromethyl-2H-pyrazol-3- yl) -piperidin- 1 -yl] -3,3,3- Hydroxy-2-methyl-propan-1-one ("A43 &

Example "A43" was prepared as described for example "A35 ".

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 104 mg (55%) colorless solid; (Purity 100%, Rt: 2.39 min, (M + H) 436.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.66 - 7.50 (m, 5H), 7.06 - 6.96 (m, 1H), 6.94 - 6.79 (m, 1H), 4.87 - 4.24 (m, 2H ), 3.06-2.52 (m, 3H), 1.89-1.73 (m, 2H), 1.70-1.40 (m, 5H).

(R) -1- {4- [l- (4-fluoro-phenyl) -lH-pyrazol-3- yl] -3-methyl-piperidin- Trifluoro-2-hydroxy-2-methyl-propan-1-one (&

44.1 3-Methyl-4- (2H-pyrazol-3-yl) -pyridine

(1.46 g; 7.634 mmol, prepared from Example 31.2) was dissolved in ethanol (12.0 mL). Hydrazinium hydroxide (371 [mu] L; 7.634 mmol) was added and the mixture was stirred at 85 [deg.] C for 48 hours. The reaction mixture was diluted with water and saturated NaHCO ₃ - solution (pH 7-8) and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash RF 200); Yield: 804 mg (66%) yellow oil.

44.2 3-methyl-4- (2H-pyrazol-3-yl) -piperidine hydrochloride

Example 34.2 Hydrogenation reaction as described for (5 bar, room temperature, 4 h)

; Yield: 876 mg (100%) colorless oil.

44.3 3-Methyl-4- (2H-pyrazol-3-yl) -piperidine- 1 -carboxylic acid tert-butyl ester

BOC-protected as described for Example 34.3; Yield: 750 mg (66%) colorless oil; Rt: 1.98 min, (M + Ht-butyl) 210.1).

44.4 3-yl] -3-methyl-piperidine-l-carboxylic acid terf-butyl ester &lt; EMI ID =

The arylation reaction and purification were carried out as described for Example 34.4; Yield: 376 mg (79%) pale yellow oil; Rt: 2.79 min, (M + Ht-butyl) 304.2.

44.5 4- [l- (4-Fluoro-phenyl) -lH-pyrazol-3-yl] -3-methyl-piperidine hydrochloride

The deprotection was carried out as described for Example 34.5; Yield: 309 mg (100%).

44.6 (R) -1- {4- [l- (4-fluoro-phenyl) -lH-pyrazol-3- yl] -3-methyl-piperidin- Trifluoro-2-hydroxy-2-methyl-propan-1-one (&

The acylation reaction was carried out as described in example 27; Yield: 409 mg (89%) as a colorless solid; Mixtures of diastereomers; (Purity 98.5%, Rt: 2.36 min, (M + H) 400.2).

The following compounds were prepared analogously:

(3R, 4R) -4- [l- (4-fluoro-phenyl) -lH- pyrazol-3-yl] Yl} -2-hydroxy-2-methyl-propan-1-one ("A45")

(R) -3,3,3-trifluoro-l- {(3S, 4S) -4- [l- (4- fluoro-phenyl) Yl} -2-hydroxy-2-methyl-propan-1-one ("A46 &

"A44" was isolated as a single diastereomer by chiral chromatography (column: Chiralpak AD-H, solvent: CO ₂ + 10% MeOH + 0.5% diethylamine).

Yield ("A45"): 100 mg (25%) colorless oil; (Purity 100%, Rt: 2.36 min, (M + H) 400.2); HPLC (Chiralpak AD-H; CO ₂ / MeOH / diethylamine-95/5 / 0.5): Rt 3.83 min; ^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 8.44 (d, J = 2.5 Hz, 1H), 7.94 - 7.84 (m, 2H), 7.44 - 7.34 (m, 2H), 7.25 - 6.95 ( 2H), 2.34-2.15 (m, 2H), 3.47-3.40 (m, 1H), 6.46 (d, J = 2.5 Hz, 1H), 2.15-1.94 (m, 1H), 1.94-1.83 (m, 1H), 1.63 (s, 3H), 0.88-0.63 (m, 3H).

Yield ("A46"): 122 mg (30%) colorless oil; (Purity 98.5%, Rt: 2.35 min, (M + H) 400.2); HPLC (Chiralpak AD-H; CO ₂ / MeOH-95/5): Rt 5.61 min;

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.37 (d, J = 2.5 Hz, 1H), 7.88 - 7.78 (m, 2H), 7.36 - 7.26 (m, 2H), 7.02 (s, 1H), 6.38 (d, J = 2.5 Hz, 1H), 4.81-3.55 (m, 2H), 3.44-3.11 (m, , 2.02-1.85 (m, 1H), 1.85-1.71 (m, 1H), 1.55 (s, 3H), 0.84-0.56 (m, 3H).

(R) -1- [4- (5-methyl-l-phenyl-lH-pyrazol-3- yl) -piperidin- l-yl] -3,3,3-trifluoro- Methyl-propan-1-one ("A47")

"A47" was prepared as described for example "A34 ".

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 8 mg (12%) colorless solid; (Purity 100%, Rt: 2.20 min, (M + H) 382.2);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.53 - 7.46 (m, 4H), 7.42 - 7.35 (m, 2H), 7.03 (s, 1H), 6.14 (s, 1H), 4.81 - 2H), 3.19-3.04 (m, 1H), 2.95-2.67 (m, 2H), 2.30 (s, 3H), 2.00-1.87 (m, 2H), 1.64-1.42 (m, 5H).

(3-chloro-4-methoxy-phenyl) -2H-pyrazol-3-yl] - Yl} -2-methyl-propan-1-one ("A48")

Prepared according to the procedure described for example "A1 "; Yield: 188 mg (62%), colorless solid; (Purity: 99%, Rt: 2.14 min, (M + H) 432.1-434.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.54 (d, J = 2.2 Hz, 2H), 7.42 (dd, J = 8.8, 2.6 Hz, 1H), 7.27 (d, J = 8.8 Hz 2H), 3.94 (s, 3H), 3.06-2.82 (m, 2H), 2.69-2.51 (m, , &Lt; / RTI &gt; 1H), 1.87-1.70 (m, 2H), 1.62-1.35 (m, 5H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- (4- {2- [4- (2,2,2- trifluoro-ethoxy) -phenyl ] -2H-pyrazol-3-yl} -piperidin- 1 -yl) -propan-1-one (&

Prepared according to the procedure described in example "A1 "; Yield: 251 mg (64%), colorless solid; (Purity: 99%, Rt: 2.24 min, (M + H) 466.2);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.54 (d, J = 1.8 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.24 - 7.16 (m, 2H), 7.00 (s, 1H), 6.33-6.25 (m, 1H), 4.85 (q, J = 8.8 Hz, 2H), 4.80-4.27 (m, 2H), 3.03-2.84 , 1.86-1.70 (m, 2H), 1.62-1.38 (m, 5H).

(4-chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] -piperidin- Fluoro-2-hydroxy-2-methyl-propan-1-one ("A50 &

50.1 4- [2- (4-Chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] -piperidine

4-Chlorophenylhydrazine hydrochloride (140.4 mg, 0.784 mmol) was added to a solution of 4- (3-oxo-butyryl) -piperidine-l-carboxylic acid tert- 5.0 mL) and the solution was heated to reflux for 3 hours. The mixture was cooled to room temperature and evaporated under reduced pressure. The crude residue was purified by flash chromatography (CombiFlash RF 200).

Yield: 38 mg (14%) of a yellow oil, tert-butyl 4 - [l- (4-chloro-phenyl) -5- methyl- lH- pyrazol- 3- yl] -piperidine- ester;

Yield: 24 mg (12%) yellow oil (12%), 4- [2- (4-chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] -piperidine;

Yield: 140 mg (69%) yellow oil / solid (crystallization on standing)

50.2 (4-chloro-phenyl) -5-methyl-2H-pyrazol-3-yl] -piperidin- Fluoro-2-hydroxy-2-methyl-propan-1-one ("A50 &

The acylation reaction was carried out as described for example "A1 ".

Purification by RP-flash chromatography (CombiFlash RF 200).

Yield: 136 mg (67%) as a colorless solid; (Purity 99.5%, Rt: 2.22 min, (M + H) 416.2-418.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.60 - 7.54 (m, 2H), 7.50 - 7.45 (m, 2H), 7.01 (s, 1H), 6.13 (s, 1H), 4.85 - 2H), 1.61-1.36 (m, 5H), 4.29 (m, 2H), 3.04-2.88 (m, 2H), 2.66-2.51 (m,

(R) -1- [4- (2-cyclopentyl-2H-pyrazol-3- yl) -piperidin- 1 -yl] -3,3,3-trifluoro-2- Methyl-propan-1-one ("A51")

Preparation and purification as described for example "A17 ".

Yield: 55 mg (11%), colorless solid; (Purity 99.1%, Rt: 3.73 min);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.32 (d, J = 1.5 Hz, 1H), 7.07 (s, 1H), 5.99 (s, 1H), 4.76-4.71 (m, 1H) 2H), 1.90-1.84 (m, 7H), 1.61-1.58 (m, 2H) m, 2H), 1.52-1.35 (m, 5H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- (2-methyl-2H-pyrazol-3- yl) -piperidin- ] -Propan-1-one ("A52")

Preparation and purification as described in example "A17 ".

Yield: 98 mg (11%), brown solid; (Purity 99.5%, Rt: 2.45 min);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.27 (d, J = 1.8 Hz, 1H), 7.08 (s, 1H), 6.03 (s, 1H), 4.79-4.78 (m, 1H) (M, 1H), 2.47-2.67 (m, 1H), 1.89-1.87 (m, 2H), 1.63-1.30 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-1- {4- [2- (6-methoxy- Piperazin-1-yl} -2-methyl-propan-1-one (&

Preparation and purification as described for example "A17 ".

Yield: 15 mg (8%), colorless solid; (Purity 98%, Rt: 3.54 min);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.22 (d, J = 2.0 Hz, 1H), 7.68-7.66 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 6.25 (m, 2H), 1.72 (m, IH), 5.13-5.11 (m, IH), 4.49-4.47 -1.62 (m, 5H).

2-Hydroxy-2-methyl-propionyl) -piperidin-4-yl] -4- Dihydro- [1,2,4] triazol-3-one ("A54")

54.1 N- (l-Benzyl-piperidin-4-yl) -2-fluoro-benzamide

4-Amino-N-benzylpiperidine (0.87 mL; 4.613 mmol) and N-ethyldiisopropylamine (1.43 mL; 8.388 mmol) were dissolved in dichloromethane (2 mL). This solution was added dropwise to a solution of the dissolved 2-fluorobenzoyl chloride (0.50 mL; 4.194 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 ° C for 1 hour. The mixture was diluted with dichloromethane, extracted with 1N HCl, and washed with 2N NaOH and water. The organic phase was dried over MgSO ₄ and concentrated under reduced pressure. The product was used in the next step without further purification; Yield: 1.04 g (79%).

54.2 N '- [l- (l-Benzyl-piperidin-4-ylamino) -l- (2- fluoro-phenyl) -meth- (E) -ylidene] -hydrazinecarboxylic acid tert- butyl ester

(1.040 g; 3.329 mmol) was dissolved in toluene (20.0 mL) and phosphorus pentachloride (832.0 mg; 3.995 mmol) was added dropwise to a solution of N- (1-benzyl-piperidin- ) Was added under nitrogen. The mixture was refluxed at 130 &lt; 0 &gt; C for 4 hours. The solvent was removed and the residue was dissolved in dry THF (40.0 mL). This solution was added dropwise to a solution of hydrazinecarboxylic acid tert-butyl ester (792.0 mg; 5.993 mmol) in dry THF (40.0 mL) at 0 ° C. After the addition was complete, the mixture was stirred at 25 &lt; 0 &gt; C for 14 hours. The reaction mixture was evaporated to dryness and the residue was used without further purification in the next step; Yield: 808 mg (57%).

54.3 N'-Amino-N- (1-benzyl-4-piperidyl) -2-fluoro-benzamidine

N '- [l- (l-Benzyl-piperidin-4-ylamino) -l- (2- fluoro-phenyl) -meth- (E) -ylidene] -hydrazinecarboxylic acid tert- butyl Ester (808.0 mg; 1.894 mmol) was dissolved in HCl solution (4.0 M in dioxane; 20.0 mL) and stirred at 25 째 C for 20 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The combined organic phases were washed with 2N sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness. The residue was used without further purification in the next step; Yield: 600 mg (97%).

54.4 4- (l-Benzyl-piperidin-4-yl) -5- (2- fluoro-phenyl) -2,4- dihydro- [1,2,4] triazol-

1,1'-carbonyldiimidazole (124.9 mg; 0.770 mmol) was dissolved in THF (80 mL) and warmed to 50 &lt; 0 &gt; C. (200.0 mg; 0, 613 mmol) was dissolved in THF (50 mL) and treated over 2 h with a solution of 2-amino-N- I fell. Thereafter, the reaction mixture was stirred for 1 hour without heating. The mixture was diluted with dichloromethane, extracted with 1N NaOH and water, dried over magnesium sulfate and concentrated under reduced pressure; Yield: 30 mg (14%).

54.5 Phenyl) -4-piperidin-4-yl-2,4-dihydro- [1,2,4] triazol-

Phenyl) -2,4-dihydro- [1,2,4] triazol-3-one (50.0 mg, ; 0.142 mmol) was dissolved in THF (10 mL) and hydrogenated over Pd / C at atmospheric pressure and room temperature for 14 h. The reaction mixture was evaporated under reduced pressure and the residue was used without further purification in the next step; Yield: 35 mg (94%).

54.6 2-Hydroxy-2-methyl-propionyl) -piperidin-4-yl] -4- Dihydro- [1,2,4] triazol-3-one ("A54")

4-yl-2,4-dihydro- [1,2,4] triazol-3-one (35.0 mg, 0.133 mmol) and 5- (2- Hydroxy-2-methyl-propionic acid (25.3 mg, 0.160 mmol) was dissolved in DMF (1.0 mL) and the mixture was cooled in an ice bath. HATU (76.1 mg; 0.200 mmol) and N-ethyldiisopropylamine (0.06 ml; 0.334 mmol) were added, cooling was removed and the mixture was stirred at 25 <0> C for 20 h. The reaction was evaporated and the residue was purified by RP-flash-chromatography; Yield: 10 mg (18%) as a pale yellow solid; (Purity: 100%, Rt: 1.73 min, (M + H) 403.1);

^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 12.01 (s, 1H), 7.69 - 7.63 (m, 1H), 7.57 (td, J = 7.5, 1.8 Hz, 1H), 7.47 - 7.40 ( 2H), 3.79-3.68 (m, 1H), 3.17-3.03 (m, 1H), 7.38 (td, J = 7.5, 1.1 Hz, 1H), 2.99-2.85 (m, 1H), 2.60-2.54 (m, 1H), 2.36-2.09 (m, 1H), 1.77-1.63 (m, 2H), 1.48

(R) -3,3,3-Trifluoro-1- {4- [3- (2-fluoro- phenyl) - [1,2,4] triazol- 4- yl] -piperidin- Yl} -2-hydroxy-2-methyl-propan-1-one (&

55.1 L-Benzyl-4- [3- (2-fluoro-phenyl) - [l, 2,4] triazol-4- yl] -piperidine

4-sulfonic acid monohydrate (61.1 mg, 0.355 mmol) and dimethoxy-methyl-dimethyl-amine (0.54 mL; 4.068 mmol) were added to a solution of N'-amino- ) -2-fluoro-benzamidine (1.0 g; 3.064 mmol) in dry toluene (0.35 mL). The reaction mixture was refluxed for 14 h using a Dean-Stark-apparatus and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with sodium carbonate solution and water, dried over magnesium sulfate and concentrated in vacuo. The oily residue was purified by RP-chromatography; Yield: 250 mg (24%).

55.2 4- [3- (2-Fluoro-phenyl) -1,2,4-triazol-4-yl] -piperidine

Hydrogenation as described for example 54 (step 54.5). The product was used in the next step without further purification; Yield: 150 mg (82%).

55.3 (R) -3,3,3-Trifluoro-1- {4- [3- (2-fluoro- phenyl) - [1,2,4] triazol- 4- yl] -piperidin- Yl} -2-hydroxy-2-methyl-propan-1-one (&

The acylation reaction was carried out as described for Example 54 (step 54.6); Purification RP-Flash-chromatography; Yield: 23 mg (10%) colorless solid; (Purity: 100%, Rt: 1.68 min, (M + H) 387.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.91 (s, 1H), 7.71 - 7.64 (m, 1H), 7.59 (td, J = 7.5, 1.8 Hz, 1H), 7.49 - 7.38 ( (m, 2H), 7.06 (s, 1H), 4.89-4.36 (m, 2H), 4.13-4.00 (m, 1H), 3.13-2.57 s, 3H).

(R) -1- {4- [3- (4-chloro-phenyl) - [l, 2,4] triazol-4- yl] -piperidin- Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A56 &

56.1 4- (4-Chloro-benzoylamino) -piperidine-l-carboxylic acid ethyl ester

4-Chlorobenzoyl chloride (0.551 mL; 4.285 mmol) was dissolved in dry dichloromethane (7.5 mL) and treated with 5 &lt; RTI ID = 0.0 & Over a period of one minute. The temperature increased from room temperature to 35 캜 during the addition, and a pale brown precipitate formed. The reaction mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was diluted with dichloromethane, washed with saturated NaHCO ₃ solution and brine, dried with sodium sulfate, filtered with suction and evaporated to dryness. The solid residue was triturated with diethyl ether, filtered through suction, washed with diethyl ether and dried; Yield: 929 mg (70%); (Purity: 98.2%, Rt: 2.02 min, (M + H) 311.1).

The following steps (56.2 - 56.4) were carried out as described for example "A54" (steps 54.2-54.3) and example "A55" (step 55.1).

56.5 4- [3- (4-chloro-phenyl) - [1,2,4] triazol-4-yl] -piperidine

Carboxylic acid ethyl ester (305.0 mg, 0.911 mmol) was dissolved in chloroform (5 mL) 7.5 mL) and iodotrimethylsilane (0.248 mL; 1.822 mmol) was added under argon. The reaction mixture was stirred at 55 [deg.] C for 14 hours. The reaction mixture was diluted with dichloromethane, washed with 2N NaOH and brine, dried over sodium sulfate, filtered through suction and evaporated to dryness; Yield: 163 mg (68%).

56.6 (R) -1- {4- [3- (4-chloro-phenyl) - [l, 2,4] triazol-4- yl] -piperidin- Trifluoro-2-hydroxy-2-methyl-propan-1-one

Acylation was carried out as described in example "A54" (step 54.6). Purification by flash chromatography (Companion RF, 12 g Si50 silica gel column DCM / MeOH (5%)); Yield: 107 mg (43%); (Purity: 100%, Rt: 1.84 min, (M + H) 403.1-405.1); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.66 (s, 1H), 7.71 - 7.49 (m, 4H), 6.66 (s, 1H), 4.71 - 4.54 (m, 2H), 4.43 - 2H), 2.18-1.96 (m, 2H), 1.96-1.78 (m, 2H), 1.58 (s, 3H).

(R) -3,3,3-Trifluoro-2-hydroxy-1- {4- [3- (4-methoxy- phenyl) -3H- [1,2,3] triazol- Yl} -2-methyl-propan-1-one ("A57 &

57.1 Phenyl] -3H- [1,2,3] triazol-4-yl] -piperidine-l-carboxylic acid tert-butyl ester

(300.1 mg, 1.167 mmol) and 4-azidinium anisole (191.4 mg; 1.284 mmol) were dissolved in dioxane (4.0 mL) . L-ascorbic acid sodium salt (34.7 mg; 0.175 mmol) was dissolved in water (0.2 mL) and added to the yellow solution with stirring. The reaction solution was purged with argon and copper sulphate pentahydrate (6.2 mg; 0.023 mmol) was added in one portion. The suspension was purged with argon for 10 minutes and stirred at 100 &lt; 0 &gt; C for 7 hours. The suspension was filtered and the residue was washed with dioxane. The filtrate was evaporated to dryness. The oil residue was triturated with diethyl ether, the precipitate was filtered off and the filtrate was evaporated to dryness. The residue was used without further purification; Yield: 285 mg (64%) yellow oil.

57.2 4- [3- (4-methoxy-phenyl) -3H- [1,2,3] triazol-4-yl] -piperidine hydrochloride

4-yl] -piperidine-l-carboxylic acid tert-butyl ester (269.0 mg; 0.750 mmol) was obtained as colorless crystals from 4- [3- (4-methoxy- phenyl) ) Was dissolved in HCl solution (4.0 M, 4.0 mL in dioxane), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was evaporated to dryness and the oily residue was used without further purification; Yield: 214 mg (97%).

57.3 (R) -3,3,3-Trifluoro-2-hydroxy-1- {4- [3- (4-methoxy- phenyl) -3H- [1,2,3] triazol- Yl} -2-methyl-propan-1-one ("A57 &

(214.0 mg, 0.726 mmol) and (R) -3,2-dimethyl-lH-pyrrolo [2,3- 3,3-Trifluoro-2-hydroxy-2-methyl-propionic acid (229.5 mg; 1.452 mmol) was dissolved in DMF (2.5 mL). The yellow solution was cooled with a water-ice-bath. (657 mg; 5.082 mmol) was added and HATU (607 mg; 1.597 mmol) was added in one portion, cooling was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness. The oily residue was purified by RP-chromatography; Yield: 95 mg (33%) as a colorless solid; (Purity: 100%, Rt: 2.01 min, (M + H) 399.1); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.51 (s, 1H), 7.77 (d, J = 9.1 Hz, 2H), 7.12 (d, J = 9.1 Hz, 2H), 7.04 (s (M, 2H), 3.83 (s, 3H), 3.26-3.16 (m, 1H), 3.15-3.00 (m, 2H), 1.81-1.39 (m, 5H).

(4-chloro-phenyl) -3H- [1,2,3] triazol-4-yl] -piperidin- 3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A58"

Prepared according to the procedure described in example "A57 ".

Purification by preparative HPLC (Agilent®, column: SunFire ™ Prep C18 OBD ™ 5 μM; 30 x 150 mm). The pure fraction was lyophilized; yield: 39 mg (29%) as a pale yellow solid; (Purity: 100%, Rt: 2.18 min, (M + H) 403.1-405.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.51 (s, 1H), 7.91 - 7.84 (m, 2H), 7.65 - 7.57 (m, 2H), 6.72 (s, 1H), 4.58 - 4.46 (m, 2H), 3.18-3.04 (m, 3H), 2.10-2.00 (m, 2H), 1.74-1.62 (m, 2H), 1.59-1.54 (m, 3H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- (3- ) -Piperidin-1-yl] -propan-1-one ("A59 &

Prepared according to the procedure described for example "A57 ".

Purification by preparative HPLC (Agilent®, column: SunFire ™ Prep C18 OBD ™ 5 μM; 30 x 150 mm). The pure fraction was lyophilized; yield: 15 mg (22%) as a pale yellow solid; (Purity: 100%, Rt: 2.11 min, (M + H) 383.2);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.40 (s, 1H), 7.74 - 7.67 (m, 2H), 7.39 - 7.31 (m, 2H), 6.70 (s, 1H), 4.57 - 2H), 1.74-1.61 (m, 2H), 1.57-1.54 (m, 3H).

(R) -3,3,3-Trifluoro-1- {4- [3- (2-fluoro-4-methyl- ] - piperidin-1-yl} -2-hydroxy-2-methyl-

60.1 1-azido-2-fluoro-4-methyl-benzene

A solution of 2-fluoro-4-methyl-phenylamine (300.0 mg; 2.397 mmol) in glacial acetic acid (2.1 mL) and conc. To the mixture in H ₂ SO ₄ (1 mL) was added dropwise sodium nitrate (172 mg, 2.487 mmol) in water (1.5 mL) at 0-5 ° C with vigorous stirring. After 10 minutes, aqueous urea was added to the reaction mixture to remove excess sodium nitrate. Sodium azide (171 mg, 2.637 mmol) in water (1.5 mL) was then added to the reaction mixture at 0-5 C for 3 hours. The reaction mixture was stirred at room temperature for 14 hours, poured into ice water, and the resulting mixture was made basic with sodium hydroxide and extracted with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated to give the corresponding azide which was used in the next step without further purification; Yield: 150 mg (39%) brown oil; Rt: 2.50.

The following steps (60.2 - 60.3) were carried out as described in example "A57 &quot;.

60.4 (R) -3,3,3-Trifluoro-1- {4- [3- (2-fluoro-4-methyl- ] - piperidin-1-yl} -2-hydroxy-2-methyl-

Prepared according to the procedure described in example "A57 ".

Purification by preparative HPLC (Agilent®, column: SunFire ™ Prep C18 OBD ™ 5 μM; 30 x 150 mm). The pure fraction was lyophilized; Yield: 17 mg (26%) beige solid; (Purity: 99%, Rt: 2.13 min, (M + H) 401.2);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.22 (d, J = 1.9 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.25 2H), 1.76 (m, IH), 7.20 (m, IH) - 1.63 (m, 2H), 1.59 - 1.57 (m, 3H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- (2- phenyl- imidazol- 1 -yl) -piperidin- Propane-1-one ("A61")

61.1 4- (2-Phenyl-imidazol-1-yl) -piperidine-l-carboxylic acid tert-butyl ester

(100.0 mg, 0.398 mmol), iodo-benzene (105.5 mg; 0.517 mmol), palladium acetate (47% Pd; 2.7 0.012 mmol) and copper iodide (159.1 mg, 0.836 mmol) were suspended in DMF (2.0 mL). The vial was sealed with septum, argon was bubbled through the reaction mixture for 5 minutes and the mixture was stirred at 140 &lt; 0 &gt; C in a microwave apparatus for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous ammonia (15%), water and brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (Companion RF; 24 g Si50 silica gel column; DCM / MeOH (2.5%)); Yield: 153 mg (43%); (Rt: 1.51 min, (M + H) 328.2).

61.2 4- (2-Phenyl-imidazol-1-yl) -piperidine trinitrifluoroacetate

Carboxylic acid tert-butyl ester (143.0 mg, 0.437 mmol) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (0.842 ml; 10.935 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was evaporated to dryness and the residue (249 mg) was used in the next step without further purification.

61.3 (R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- (2- phenyl- imidazol- 1 -yl) -piperidin- Propane-1-one ("A61")

(249.0 mg, 0.437 mmol), (R) -3,3,3-trifluoro-2-hydroxy-isoquinolin- 2-Methyl-propionic acid (138.2 mg; 0.875 mmol) and HATU (332.6 mg; 0.875 mmol) were dissolved in DMF (2.5 mL). N-ethyldiisopropylamine (565.2 mg; 4.373 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. Washing combined organic layers with saturated NaHCO ₃ solution and brine, dried with sodium sulfate, dried, filtered and evaporated. The residue was purified by flash chromatography (Companion RF, 24 g Si50 silica gel column). The resulting product was suspended in acetonitrile (1.5 mL), filtered off with suction, washed with little acetonitrile and diethyl ether and dried under vacuum at 50 ° C for 2 hours. Yield: 92.5 mg (57%) as a colorless solid; (Purity: 100%; Rt: 1.30 min, (M + H) 368.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.59 - 7.40 (m, 6H), 7.15 (s, 1H), 7.05 (d, J = 1.3 Hz, 1H), 4.89 - 4.30 (m, 3H), 3.14-2.33 (m, 1H), 2.75-2.55 (m, 1H), 2.05-1.73 (m, 4H), 1.54 (s, 3H).

(R) -1- {4- [2- (4-Chloro-phenyl) -imidazol- 1- yl] -piperidin- 1 -yl} -3,3,3-trifluoro- Methyl-propan-1-one ("A62")

Preparation according to the procedure described for example "A61 ".

Purification by flash chromatography (Companion RF, 24 g Si50 silica gel column; DCM / MeOH (2.5%)); Yield: 55 mg (68%) colorless solid; (Purity: 100%; Rt: 1.46 min, (M + H) 402.1-404.1); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.60 - 7.54 (m, 2H), 7.54 - 7.48 (m, 2H), 7.37 - 7.33 (m, 1H), 7.03 - 6.99 (m, 1H ), 6.76 (s, 1H), 4.72-4.58 (m, 2H), 4.42-4.30 (m, 1H), 2.93-2.80 (m, 2H), 2.01-1.91 , 2H), 1.59-1.52 (m, 3H).

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- (5-phenylimidazol- - on ("A63")

63.1 N - [(E) -2-phenyl-1- (toluene-4-sulfonyl) -vinyl] -formamide

Potassium tert-butylate (948 mg; 8.451 mmol) was dissolved in dry THF (12.0 mL) under argon and cooled to -40 &lt; 0 &gt; C. A solution of 1-isocyanomethane-sulfonyl-4-methyl-benzene (1.5 g; 7.683 mmol) in dry THF (6.0 mL) was added dropwise. The reaction mixture was stirred at -40 &lt; 0 &gt; C for 30 min. A solution of benzaldehyde (815 mg; 7.683 mmol) in dry THF (6.0 mL) was added dropwise while maintaining the temperature at -40 &lt; 0 &gt; C. The reaction mixture was stirred at -40 &lt; 0 &gt; C for 20 minutes. The reaction mixture was poured into ice water, neutralized with 1N HCl solution (pH = 7) and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered through suction, and evaporated to dryness. The solid residue was triturated with methyl-tert-butyl ether, filtered through suction, washed with a small amount of methyl-tert-butyl ether and diethyl ether and dried. Yield: 2.0 g (86%), light brown solid (purity: 100%; Rt: 2.04 min, (M + H) 302.1).

63.2 4- (5-Phenyl-imidazol-1-yl) -piperidine-l-carboxylic acid ethyl ester

(2.0 g; 6.637 mmol) was dissolved in dry THF (30.0 mL) and treated at -10 &lt; 0 &gt; C Lt; / RTI &gt; Triethylamine (9.2 ml; 66.366 mmol) was added and the solution was stirred for 10 minutes. Phosphoryl chloride (1.83 mL; 19.910 mmol) was added dropwise over a period of 10 min maintaining the temperature at -10 &lt; 0 &gt; C. The reaction mixture was stirred at -10 <0> C for a further 30 min. The reaction mixture was poured into ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered through suction and evaporated to dryness. The residue was dissolved in dry THF (25.0 mL) and added dropwise at room temperature to a solution of 4-amino-piperidine-l-carboxylic acid ethyl ester (2.29 g; 13.273 mmol) in methanol (15.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness. The oil residue was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate, filtered through suction and evaporated to dryness. The residue was purified by flash chromatography (Companion RF; 120 g Si50 silica gel column); Yield: 387 mg (19%) brown oil (purity: 98.3%; Rt: 1.37 min, (M + H) 300.2).

63.3 4- (5-Phenyl-imidazol-1-yl) -piperidine

1-carboxylic acid ethyl ester (387.0 mg; 1.294 mmol) was dissolved in dry THF (20.0 mL) and cooled to 0 &lt; 0 &gt; C . Methyl lithium (5% solution in diethyl ether) (2.03 mL; 3.234 mmol) was added dropwise over a period of 15 minutes under argon. The reaction mixture was stirred at 0 &lt; 0 &gt; C for a further 30 min. The reaction mixture was poured into ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered through suction and evaporated to dryness. The residue was reacted without further purification; Yield: 164 mg (56%).

63.4 (2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- (5-phenylimidazol- - on ("A63")

(164.0 mg, 0.721 mmol), (R) -3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (228.1 mg; 1.443 mmol) and HATU (548.7 mg; 1.443 mmol) were dissolved in DMF (2.5 mL). N-Ethyldiisopropyl-amine (0.613 mL; 3.607 mmol) was added and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. Washing combined organic layers with saturated NaHCO ₃ solution and brine, dried with sodium sulfate, dried, filtered and evaporated. The residue was purified by flash chromatography (Companion RF, 40 g Si50 silica gel column). The residue was triturated in a small amount of dichloromethane, filtered off with suction, washed with diethyl ether and dried under vacuum at 50 &lt; 0 &gt; C for 2 hours; Yield: 60 mg (23%) as a colorless solid; (Purity: 100%; Rt: 1.40 min, (M + H) 368.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.85 - 7.80 (m, 1H), 7.52 - 7.45 (m, 2H), 7.45 - 7.38 (m, 3H), 6.96 - 6.91 (m, 1H ), 6.77 (s, 1H), 4.72-4.88 (m, 2H), 4.33-4.22 (m, 1H), 2.91-2.78 , 2H), 1.60-1.53 (m, 3H).

(2R) -1- [4- [5- (4-chlorophenyl) imidazol-1-yl] -1-piperidyl] -3,3,3-trifluoro- Methyl-propan-1-one ("A64")

Prepared according to the procedure described for example "A63 ".

Purification by flash chromatography (Companion RF, 12 g Si50 silica gel column); Yield: 104 mg (74%) colorless solid; (Purity: 100%; Rt: 1.56 min; (M + H) 402.1-404.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.94 (s, 1H), 7.58 - 7.51 (m, 2H), 7.49 - 7.41 (m, 2H), 7.08 (s, 1H), 6.98 ( (m, 4H), 2.85-2.54 (m, 1H), 4.90-4.36 (m, 2H), 4.29-4.16 1.54 (s, 3 H).

Methyl-1- [4- (3-phenyl-3H-imidazol-4-yl) -piperidin- ] -Propan-1-one ("A65")

65.1 1- [2- (1-tert-Butoxycarbonyl-piperidin-4-yl) -2-oxo-ethyl] -3,5,7-triaza-1-azonia-tricyclo [3.3. 1.13,7] decane bromide

Carboxylic acid tert-butyl ester (500.0 mg; 1.633 mmol) was dissolved in chloroform (3.0 mL). Hexamethylenetetramine (0.172 ml; 1.633 mmol) was added and the solution was stirred at 50 &lt; 0 &gt; C for 1 hour. The reaction mixture was cooled to 0 &lt; 0 &gt; C and the resulting precipitate was filtered off with suction and washed with a small amount of dichloromethane. The filtrate was evaporated to dryness. The residue was suspended in diethyl ether, filtered off with suction, washed with diethyl ether and dried under vacuum; Yield: 725 mg (99%).

65.2 4- (2-Amino-acetyl) -piperidine-l-carboxylic acid tert-butyl ester tosylate

- [3- (1-tert-butoxycarbonyl-piperidin-4-yl) -2-oxo-ethyl] -3,5,7- triaza- 1 -azoni- a tricyclo- [3.3 .1.13,7] -decane bromide (725.0 mg; 1.625 mmol) was dissolved in ethanol (3.0 mL) and toluene-4-sulfonic acid hydrate (340.0 mg, 1788 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered by suction, washed with a small amount of ethanol and diethyl ether and dried under vacuum at 50 &lt; 0 &gt; C for 2 hours; Yield: 260 mg (39%).

 65.3 4- [2- (3-phenyl-thioureido) -acetyl] -piperidine-l-carboxylic acid tert-butyl ester

Butyl ester tosylate (121.0 mg, 0.292 mmol) was suspended in dry THF (5.0 mL) and phenylisothiocyanate (78.3 mg, mg; 0.579 mmol). Triethylamine (107.4 mg; 1.061 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 hours and at 55 占 for 1 hour. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with water and brine, dried over Na ₂ SO _4, filtered by suction, dried and evaporated. The residue was purified by flash chromatography (Companion RF; 24 g Si50 silica gel column); Yield: 45 mg (41%).

65.4 4- (3-phenyl-3H-imidazol-4-yl) -piperidine trinitrifluoroacetate

Carboxylic acid tert-butyl ester (180.0 mg, 0.477 mmol) was dissolved in glacial acetic acid (2.0 mL) and added to a solution of 4- [2- (3-phenyl- thioureido) -acetyl] -piperidine- , And refluxed for 2 hours. The reaction mixture was cooled to 0-5 &lt; 0 &gt; C and hydrogen peroxide (30%; 0.488 ml; 4.773 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at 5 &lt; 0 &gt; C to room temperature for 5 minutes. The reaction mixture was diluted with toluene and evaporated to dryness. The residue was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (0.368 mL; 4.773 mmol) was added. The solution was stirred at room temperature for 20 minutes and evaporated to dryness. The residue was used without further purification in the next step.

65.5 Methyl-1- [4- (3-phenyl-3H-imidazol-4-yl) -piperidin- ] -Propan-1-one ("A65")

The acylation reaction was carried out as described for example 61 (step 61.3).

Purification by flash chromatography (Companion RF, 24 g Si50 silica gel column). The oily residue was crystallized by trituration with acetonitrile. The crystals were filtered off with suction, washed with small amounts of acetonitrile and diethyl ether and dried under vacuum at 60 &lt; 0 &gt; C for 2 hours; Yield: 63 mg (26%); (Purity: 99.3%, Rt: 1.32 min, (M + H) 368.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.63 - 7.47 (m, 4H), 7.44 - 7.36 (m, 2H), 6.85 (s, 1H), 6.74 (s, 1H), 4.54 - 4.40 (m, 2H), 2.89-2.69 (m, 3H), 1.80-1.68 (m, 2H), 1.55-1.38 (m, 5H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- Propane-1-one ("A66")

66.1 4-pyrazol-1-yl-pyridine hydrochloride

4-Chloropyridinium chloride (500.0 mg; 3.333 mmol) and pyrazole (680.8 mg; 9.999 mmol) were dissolved in acetonitrile (5.0 mL) and refluxed for 14 days. The reaction solution was cooled to ambient temperature and the precipitate formed was filtered off with suction, washed with acetonitrile and diethyl ether and dried under vacuum at room temperature for 2 hours; Yield: 564 mg (93%).

66.2 4-pyrazol-1-yl-piperidine hydrochloride

(564.0 mg; 3.105 mmol) was dissolved in water (5.0 mL) and the mixture was hydrogenated with Rh-C (5%) at 8.3 bar and 65 ° C for 14 hours Respectively. The reaction solution was frozen in an acetone / dry ice bath and lyophilized for 14 hours; Yield: 528.5 mg (91%).

66.3 4-pyrazol-1-yl-piperidine-l-carboxylic acid tert-butyl ester

4-pyrazol-1-yl-piperidine hydrochloride (528.5 mg; 2.816 mmol) was dissolved in THF (10.0 mL) and water (5.0 mL). After addition of triethylamine (0.976 ml; 7.039 mmol), a solution of di-tert-butyl dicarbonate (0.663 ml; 3.097 mmol) in THF (5.0 mL) was added. 4- (Dimethylamino) pyridine (34.4 mg, 0.282 mmol) was added and the solution was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered by suction and evaporated to dryness. The residue was purified by RP-chromatography (Companion RF; 86 g C18 silica gel column). Yield: 292 mg (41%); (Purity: 100%, Rt: 2.01 min, (M + Ht-butyl) 196.1).

66.4 4- (5-Phenyl-pyrazol-l-yl) -piperidine-l-carboxylic acid tert-butyl ester

1-carboxylic acid tert-butyl ester (292.0 mg; 1.162 mmol), iodobenzene (355.5 mg; 1.743 mmol), tetrabutylammonium acetate (700.6 mg; mmol) and palladium acetate (36.3 mg; 0.162 mmol) were dissolved in DMA (5.0 mL). The vial was sealed with diaphragm, argon bubbled through the solution for 5 minutes, and the solution was stirred at 70 캜 for 2 days. Palladium acetate (36.3 mg; 0.162 mmol) was added and the reaction mixture was stirred at 75 &lt; 0 &gt; C for 66 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. Washing combined organic layers with saturated NaHCO ₃ solution and brine, dried over sodium sulfate, filtered by suction and evaporated to dryness. The residue was purified by flash chromatography (Companion RF; SuperFlash SF25; 55 g C18 column).

Yield: 107.5 mg (28%); (Purity: 98.4%, 2.52 min, (M + H-butyl) 272.2).

66.5 4- (5-Phenyl-pyrazol-l-yl) -piperidine ditrifluoroacetate

Carboxylic acid tert-butyl ester (107.5 mg; 0.328 mmol) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (0.631 ml; 8.189 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was evaporated to dryness; Yield: 149 mg (100%); (HPLC: 99.2%, Rt: 1.32 min; (M + H) 228.2).

66.6 (R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- Propane-1-one ("A66")

The acylation reaction was carried out as described in example "A62" (step 62.4).

Purification by preparative HPLC (Agilent®, column: SunFire ™ Prep C18 OBD ™ 5 μM; 30 x 150 mm); Yield: 73 mg (61%); (Purity: 100%, Rt: 2.17 min, (M + H) 368.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.54 - 7.40 (m, 6H), 6.84 (s, 1H), 6.28 (d, J = 1.8 Hz, 1H), 4.68 - 4.53 (m, 2H), 1.94-1.82 (m, 2H), 1.59-1.51 (m, 3H), 4.46-4.35 (m, 1H), 2.98-2.83 (m, 2H), 2.13-1.98 (m, 2H).

(4-fluoro-phenyl) -lH-imidazol-2-yl] -piperidin-l-yl} - 2-hydroxy-2-methyl-propan-1-one ("A67 &

67.1 4- (1H-Imidazol-2-yl) -piperidine-l-carboxylic acid tert-butyl ester

4-Formylpiperidine-1-carboxylic acid tert-butyl ester (3.23 g; 15.145 mmol) was dissolved in methanol (6,74 ml; 11,000 aq.). After adding ammonium hydroxide solution (32%; 17.40 mL) and glyoxal (30% in water; 2.57 mL; 15.902 mol) after 5 minutes, the solution was stirred at room temperature for 14 hours. The reaction was diluted with brine and water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to dryness. The oily residue was purified by flash chromatography (CombiFlash RF 200); Yield: 1.73 g (45%).

67.2 4- [l- (4-Fluoro-phenyl) -lH-imidazol-2-yl] -piperidine- 1 -carboxylic acid tert-butyl ester

(251.3 mg; 1.000 mmol), 4-fluorophenylboronic acid (285.6 mg, 2.000 mmol), anhydrous (4-fluorobenzyloxy) Copper acetate (286.8 mg; 1.500 mmol) and a small amount of molecular sieve 4 Å were suspended in dry dichloromethane (6.0 mL). Dry pyridine (0.163 ml; 2.000 mmol) was added and the reaction was stirred at ambient temperature for 2 days. The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography (CombiFlashRF 200); Yield: 166 mg (43%); Rt: 1.7 min, (M + H) 346.2.

67.3 4- [l- (4-Fluoro-phenyl) -lH-imidazol-2-yl] -piperidine

A solution of hydrogen chloride (4.0 M in dioxane, 3.0 mL) was added to a stirred solution of 4- [l- (4-fluoro-phenyl) -lH-imidazol-2-yl] -piperidine -1-carboxylic acid tert-butyl ester (144.0 mg; 0.417 mmol) and the mixture was stirred at ambient temperature for 14 days. The reaction mixture was diluted with water, diluted with saturated aqueous NaHCO ₃ - solution (pH 8) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo; Yield: 62 mg (61%).

67.4 (4-fluoro-phenyl) -lH-imidazol-2-yl] -piperidin-l-yl} - 2-hydroxy-2-methyl-propan-1-one ("A67 &

(62.0 mg, 0.253 mmol), (R) -3,3,3-trifluoro-2 (4-fluoro- (40.0 mg; 0.253 mmol) and HATU (105.7 mg; 0.278 mmol) were dissolved in DMF (10.0 mL). N-Ethyldiisopropylamine (0.218 mL; 1.264 mmol) was added and the solution stirred at room temperature for 14 hours. The mixture was evaporated to dryness and the residue was purified by flash chromatography (CombiFlashRF 200); Yield: 46 mg (47%); (Purity: 100%), Rt: 1.41 min, (M + H) 386.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.52 - 7.46 (m, 2H), 7.43 - 7.35 (m, 2H), 7.20 (d, J = 1.3 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J = 1.3 Hz, 1H), 4.77-4.20 (m, 2H) , &Lt; / RTI &gt; 1.50 (s, 3H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- (1- -Yl] -propan-1-one ("A68")

Prepared according to the procedure described in example "A67 ".

Yield: 128 mg (53%); (Purity: 100%, Rt: 1.47 min, (M + H) 382.2);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.38 - 7.32 (m, 2H), 7.32 - 7.27 (m, 2H), 7.17 (d, J = 1.4 Hz, 1H), 7.03 (s, 2H), 2.72-2.53 (m, 1H), 2.39 (s, 3H), 1.84 (m, - 1.55 (m, 4 H), 1.51 (s, 3 H).

(4-chloro-phenyl) -lH-imidazol-2-yl] -Hydroxy-2-methyl-propan-1-one ("A69 &

Prepared according to the procedure described in example "A67 ".

Yield: 23 mg (22%); (Purity: 100%, Rt: 1.52 min, (M + H) 402.1 - 404.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.65 - 7.59 (m, 2H), 7.51 - 7.44 (m, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.03 (s, 2H), 3.16-2.81 (m, 2H), 2.78-2.53 (m, 1H), 1.86-1.44 (m, 4H) , &Lt; / RTI &gt; 1.51 (s, 3H).

(R) -3,3,3-trifluoro-2-hydroxy-l- {4- [l- (4- methoxy- phenyl) -lH- imidazol- 2- yl] -piperidin- Yl} -2-methyl-propan-1-one ("A70 &

Prepared according to the procedure described in example "A67 ".

Yield: 90 mg (42%); (Purity: 100%, Rt: 1.44 min, (M + H) 398.3);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.42 - 7.34 (m, 2H), 7.28 (s, 1H), 7.16 - 7.06 (m, 3H), 7.03 (s, 1H), 4.81 - 2H), 3.83 (s, 3H), 3.09-2.84 (m, 2H), 2.75-2.54 (m, 1H), 1.85-1.56 (m, 4H), 1.51 (s, 3H).

(R) -3,3,3-Trifluoro-1- {4- [4- (4-fluoro- phenyl) -4H- [1,2,4] triazol- Yl} -2-hydroxy-2-methyl-propan-1-one (&

71.1 4- [1,3,4] oxadiazol-2-yl-piperidine-l-carboxylic acid tert-butyl ester

(1.40 g; 5.754 mmol) was suspended in trimethylorthoformate (10.0 mL), and toluene-4-sulfonic acid monohydrate ( 109.5 mg; 0.575 mmol) and the mixture was refluxed at 130 &lt; 0 &gt; C for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash RF 200).

Yield: 1.04 g (71%); Rt: 1.78 min, (M + H-t-butyl) 198.1.

71.2 4- [4- (4-Fluoro-phenyl) -4H- [1,2,4] triazol-3-yl] -piperidine- 1 -carboxylic acid tert-butyl ester

(188.0 mg; 0.742 mmol) and trifluoroacetic acid (0.058 mL; 0.742 mmol) in anhydrous tetrahydrofuran (2 mL) was added to a solution of 4- [1,3,4] oxadiazol- The mixture was dissolved in toluene (3.0 mL). 4-Fluorouaniline (165.0 mg; 1.484 mmol) was added and the mixture was stirred at 110 &lt; 0 &gt; C for 14 hours. The mixture was concentrated in vacuo and the residue was purified by RP-flash chromatography (CombiFlashRF 200); Yield: 151 mg (59%) as a colorless oil; (Purity 98%, Rt: 2.03 min, (M + H) 347.2).

71.3 4- [4- (4-Fluoro-phenyl) -4H- [1,2,4] triazol-3-yl] -piperidine hydrochloride

BOC-deprotection was performed as described for example "A32" (step 32.3). The isolated product was used in the next step without further purification.

71.4 (R) -3,3,3-Trifluoro-1- {4- [4- (4-fluoro- phenyl) -4H- [1,2,4] triazol- Yl} -2-hydroxy-2-methyl-propan-1-one (&

The acylation reaction was carried out as described for example "A27 ".

Yield: 74 mg (42%); (Purity: 100%, Rt: 1.75 min, (M + H) 387.2);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.61 (s, 1H), 7.65 - 7.55 (m, 2H), 7.49 - 7.39 (m, 2H), 7.06 (s, 1H), 4.79 - 2H), 3.15-2.89 (m, 2H), 2.84-2.57 (m, 1H), 1.88-1.57 (m, 4H), 1.51 (s, 3H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- Piperazin-1-yl] -propan-1-one ("A72 &

Prepared according to the procedure described in example "A71 ".

Yield: 55 mg (50%); (Purity: 100%, Rt: 1.70 min, (M + H) 369.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.63 (s, 1H), 7.65 - 7.49 (m, 5H), 7.07 (s, 1H), 4.82 - 4.16 (m, 2H), 3.17 - 2.92 (m, 2H), 2.82-2.56 (m, 1H), 1.89-1.57 (m, 4H), 1.50 (s, 3H).

(4-chloro-phenyl) -4H- [1,2,4] triazol-3-yl] -piperidin- 3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A73"

Prepared according to the procedure described for example "A71 ".

Yield: 165 mg (67%); (Purity: 100%, Rt: 1.89 min, (M + H) 403.1-405.1);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 9.19 (s, 1H), 7.77 - 7.63 (m, 4H), 7.47 - 6.73 (m, 1H), 4.80 - 4.17 (m, 2H), 3.18-2.98 (m, 2H), 2.81-2.59 (m, 1H), 1.90-1.60 (m, 4H), 1.51 (s, 3H).

The following compounds were prepared analogously:

(R) -1- [4- (2-cyclopropyl-2H-pyrazol-3-yl) -1-piperidyl] -3,3,3-trifluoro- -Propan-1-one ("A74")

Purification by preparative HPLC; Yield: 65 mg (9%) as a pale yellow solid; (Purity 98.9%, Rt: 2.87 min, (M + H) 332.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.23 (d, J = 1.4 Hz, 1H), 7.08 (s, 1H), 6.04 (s, 1H), 4.81-4.79 (m, 1H) (M, 2H), 1.55-1.40 (m, 3H), 4.47-4.45 (m, 1H), 3.61-3.56 m, 5H), 1.22-1.03 (m, 2H), 0.99-0.95 (m, 2H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- {4- [2- (1 -methyl-piperidin- 3-yl] -piperidin-1-yl} -propan-1-one ("A75"

Purification by preparative HPLC; Yield: 5 mg (1%) as a pale yellow solid; (Purity 97.7%, Rt: 2.51 min, (M + H) 389.2); 1H (400 MHz, MeOH-d 4) δ [ppm] 7.40 (d, J = 1.9 Hz, 1H), 6.09 (d, J = 1.9 Hz, 1H), 4.89-4.88 (m, 1H), 4.62-4.60 (m, 2H), 2.36-2.27 (m, 7H), 1.96-1.86 (m, 2H), 3.15-3.13 (m, , 1.63-1.62 (m, 2H), 1.50-1.41 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-1- [4- (2-isobutyl-1H-pyrazol- -Propan-1-one ("A76")

76.1 (4- (2H-Pyrazol-3-yl) -piperidine-l-carboxylic acid tert-butyl ester

(2.00 g; 7.02 mmol) and hydrazine monohydrate (0.69 mL; 14.04 mmol) were added to a solution of 4 - ((E) -3-dimethylamino-acryloyl) -piperidine-l-carboxylic acid tert- The stirred solution in ethanol (20.00 mL) was heated at 80 &lt; 0 &gt; C for 3 hours. The reaction mixture was concentrated and the residue was diluted with dichloromethane (50 mL) and washed with water (30 mL). The aqueous layer was back-extracted with dichloromethane (2 x 15 mL). The combined organic layers washed with a brine (10 mL), and Na ₂ SO ₄ and the drying, it was concentrated under vacuum, 4- (2H- pyrazol-3-yl) -piperidine-1-carboxylic acid tert- Butyl ester (1.60 g; 6.22 mmol; 89%). The crude product was used without further purification in the next step.

76.2 (4- (2-isobutyl-2H-pyrazol-3-yl) -piperidine- 1 -carboxylic acid tert- ) -Piperidine-l-carboxylic acid tert-butyl ester

To a stirred solution of 4- (2H-pyrazol-3-yl) -piperidine-l-carboxylic acid tert-butyl ester (1.0 g; 3.887 mmol) in DMF (5.0 mL) ; 11.662 mmol). 1-Bromo-2-methyl-propane (1.08 g; 7.775 mmol) was slowly added over a period of 15 minutes and the reaction mixture was stirred at 110 &lt; 0 &gt; C for 14 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography. The obtained product (2.5 g; 16%) was a mixture of two regioisomers, which was taken to the next step without isolation.

76.3 (4- (2-isobutyl-2H-pyrazol-3-yl) -piperidine)

The cleavage of the BOC-group was carried out as described before the treatment of the crude mixture of the two positional isomers (300 mg; pale yellow oil), which was taken off in the next step.

76.4 (R) -3,3,3-Trifluoro-2-hydroxy-1- [4- (2-isobutyl-2H-pyrazol-3- yl) -piperidin- Methyl-propan-l-one &lt; / RTI &gt;

Manufacture as described above; The crude residue was purified by preparative HPLC; Yield: 10 mg (4%) brown gum); (Purity 95.8%, Rt: 3.76 min, (M + H) 348.3); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.54 (d, J = 2.0 Hz, 1H), 7.04 (s, 1H), 6.04 (s, 1H), 4.68-4.65 (m, 1H) 2H), 3.18-3.14 (m, 1H), 2.83-2.75 (m, 2H), 2.08-2.01 (m, 1H), 1.90 -1.88 (m, 2H), 1.51-1.40 (m, 5H), 0.80 (d, J = 6.68 Hz, 6H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- {4- [2- (2,2,2-trifluoro- ethyl) -2H- 3-yl] -piperidin-1-yl} -propan-1-one ("A77"

Purification by preparative HPLC; Yield: 40 mg (5%) colorless solid; (Purity 99.2%, Rt: 3.65 min, (M + H) 374.0); ¹ H NMR (400 MHz, DMSO-d ₆ )? [Ppm] 7.46 (d, J = 1.8 Hz, 1 H), 7.07 (s, 2H), 4.83-4.81 (m, IH), 4.48-4.46 (m, IH), 3.10-3.08 (m, 2H), 2.79-2.76 -1.35 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-1- [4- [2- (2-methoxyethyl) -2H- pyrazol-3-yl] ] -2-methyl-propan-1-one ("A78 &

Purification by preparative HPLC; Yield: 105 mg (15%) colorless oil; (Purity 98.2%, Rt: 2.84 min, (M + H) 350.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.33 (d, J = 1.7 Hz, 1H), 7.06 (s, 1H), 6.03 (s, 1H), 4.80-4.78 (m, 1H) 2H), 3.65 (t, J = 5.4 Hz, 2H), 3.18 (s, 3H), 3.05-3.03 2.71-2.69 (m, 1H), 1.86-1.84 (m, 2H), 1.52-1.30 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- {4- [2- Yl} -propan-1-one ("A79")

Purification by preparative HPLC; Yield: 18 mg (36%) pale brown solid; (Purity 97.5%, Rt: 2.51 min, (M + H) 383.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.56 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J = 8.2 Hz (M, 3H), 2.56 (s, 3H), 2.54 (s, 3H) ), 1.82-1.79 (m, 2H), 1.50-1.45 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- [6- (trifluoromethyl) Yl] -1-piperidyl] propan-1-one ("A80 &

Purification by column chromatography and finally grinding with hexane; Yield: 165 mg (47%) as a colorless solid; (Purity 97.2%, Rt: 4.24 min, (M + H) 437.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.97 (d, J = 2.0 Hz, 1H), 8.28-8.26 (m, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.06-7.05 (m, IH), 6.48 (brs, IH), 4.73-4.71 (m, IH), 4.41-4.39 , 2H), 2.68-2.63 (m, 1H), 1.88-1.85 (m, 2H), 1.52-1.40 (m, 5H).

2-methyl-propionyl) -piperidin-4-yl] - pyrazole-l- Yl} -pyridine-2-carbonitrile ("A81")

Yield: 13 mg (32%) as a pale yellow solid; (Purity 94.6%, Rt: 3.58 min, (M + H) 394.0);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.96-8.94 (m, 1H), 8.25 (d, J = 1.1 Hz, 2H), 7.74 (d, J = 1.72 Hz, 1H), 7.05 (s, 1H), 6.48 (m, 1H), 4.72-4.70 (m, 1H), 4.40-4.38 2H), 1.50-1.40 (m, 5H).

(R) -1- [4- [2- (3,5-difluoro-2-pyridyl) -2H-pyrazol- Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A82 &

Purification by RP-flash chromatography (CombiFlash RF 200); Yield: 66 mg (29%) as a colorless solid; (Purity 100%, Rt: 1.93 min, (M + H) 405.1); 1H NMR (500 MHz, DMSO- d 6) δ [ppm] 8.56 (d, J = 2.5 Hz, 1H), 8.34-8.27 (m, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.02 ( (m, 2H), 2.68-2.41 (m, 1H), 1.88-1.70 (m, 2H) 2H), 1.65-1.37 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- {4- [2- Yl} -propan-1-one ("A83")

Purification by column chromatography and finally grinding with hexane;

Yield: 20 mg (6%) colorless solid; (Purity 99.6%, Rt: 3.92 min, (M + H) 383.0);

^{1 H NMR (400 MHz, MeOH} -d 4) δ [ppm] 8.37 (s, 1H), 7.84-7.81 (m, 1H), 7.62 (d, J = 8.0 Hz, 2H), 6.36 (s, 1H) 1H), 2.42 (s, 1H), 2.42-2.28 (m, 1H) 3H), 2.06-2.03 (m, 2H), 1.70-1.50 (m, 5H).

Methyl-1- {4- [2- (5-trifluoromethyl-pyridin-2-yl) -2H-pyrazole Yl] -piperidin-1-yl} -propan-1-one ("A84"

Purification by basic alumina chromatography; Yield: 110 mg (68%) as a pale yellow solid; (Purity 99.1%, Rt: 4.95 min, (M + H) 437.3); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.92 (s, 1H), 8.39-8.36 (m, 1H), 8.07 (d, J = 8.80 Hz, 1H), 7.76 (d, J = (M, 1H), 3.91 (t, J = 11.20 Hz, IH), 4.84 (s, 3.32-3.31 (m, 1H), 3.10-3.01 (m, 1H), 2.06-1.98 (m, 2H), 1.53-1.50 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- Yl] -1-piperidyl] propan-1-one ("A85 &

Purification by column chromatography; Yield: 285 mg (48%) as a pale yellow solid; (Purity 99.5%, Rt: 4.18 min, (M + H) 372.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.08 (s, 1H), 7.68 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.06 (s, 1H), 6.25 (s, 3H), 3.05-2.93 (m, 2H), 2.70-2.59 (m, IH) 1.90-1.70 (m, 2H), 1.60-1.35 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- Yl] -1-piperidyl] propan-1-one ("A86 &

Purification by column chromatography; Yield: 120 mg (31%) as a pale yellow solid; (Purity 98.3%, Rt: 4.53 min, (M + H) 389.0); ¹ H NMR (400 MHz, DMSO-d ₆ )? [Ppm] 7.69 (d, J = 1.6 Hz, 1H), 7.08-7.07 (m, 2H), 6.43 (br s, 1H), 4.83-4.81 1H), 2.35 (s, 3H), 2.07-2.05 (m, IH), 4.50-4.48 (m, 2H), 1.65 - 1.53 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-1- {4- [2- (lH-imidazol- Yl} -2-methyl-propan-1-one ("A87 &

(R) -3,3,3-Trifluoro-1- [4- [2- [2-fluoro-4- (trifluoromethyl) phenyl] -2H- -Piperidyl] -2-hydroxy-2-methyl-propan-1-one (&

Purification by column chromatography; Yield: 130 mg (25%) as a colorless solid; (Purity 97.2%, Rt: 4.66 min, (M + H) 454.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.05 (d, J = 9.7 Hz, 1H), 7.81-7.76 (m, 2H), 7.69 (s, 1H), 7.05 (s, 1H) , 6.41 (br s, IH), 4.70-4.68 (m, IH), 2.98-2.96 (m, IH), 2.75-2.73 , &Lt; / RTI &gt; 2H), 1.50-1.35 (m, 6H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- [2- (trifluoromethyl) phenyl] -2H- Yl] -1-piperidyl] propan-1-one ("A89 &

Purification by column chromatography; Yield: 400 mg (51%) brown gum; (Purity 98.5%, Rt: 4.67 min, (M + H) 436.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.91-7.90 (m, 2H), 7.81 (t, J = 7.7 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.39 (d, J = 2.4 Hz, 1H), 4.67-4.65 1H), 1.96-1.94 (m, 2H), 1.70-1.52 (m, 5H).

(R) -3,3,3-Trifluoro-1- {4- [2- (4-fluoro-2-methoxy- phenyl) -2H- pyrazol-3- yl] -piperidin- Yl} -2-hydroxy-2-methyl-propan-1-one (&

Yield: 77 mg (70%) pale yellow solid; (Purity 97.5%, Rt: 3.89 min, (M + H) 416.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.51 (d, J = 1.72 Hz, 1H), 7.37 - 7.33 (m, 1H), 7.19-7.15 (m, 1H), 7.06 (s, 1H), 6.93-6.88 (m, IH), 6.24 (br s, IH), 4.69-4.67 (m, IH), 4.36-4.34 1H), 2.70-2.49 (m, 1H), 1.68-1.62 (m, 3H), 1.49-1.30 (m, 5H).

2-hydroxy-2-methyl-propanoyl] -4-piperidyl] -2H-pyrazolo [3,4- -Pyrazol-1-yl] benzonitrile ("A91")

Purification by column chromatography and finally grinding with hexane;

Yield: 30 mg (8%) as a pale yellow solid; (Purity 94.0%, Rt: 3.96 min, (M + H) 411.0);

^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.21 (dd, J = 10.0, 1.6 Hz, 1H), 7.91 (dd, J = 8.0, 1.20 Hz, 1H), 7.80 (t, J = 1H), 7.69 (d, J = 2.0 Hz, IH), 7.05 (s, IH), 6.41 (brs, IH), 4.70-4.67 (m, 2.97-2.95 (m, 2H), 2.74-2.72 (m, 1H), 1.75-1.72 (m, 2H), 1.50-1.37 (m, 5H).

(R) -3,3,3-trifluoro-1- [4- [2- [2-fluoro-4- (1- hydroxy- 1 -methyl- ethyl) phenyl] -2H- 3-yl] -1-piperidyl] -2-hydroxy-2-methyl-propan-

Purification by preparative HPLC; Yield: 45 mg (16%) as a pale yellow solid; (Purity 94.8%, Rt: 3.67 min, (M + H) 444.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.60 (d, J = 1.6 Hz, 1H), 7.52-7.47 (m, 1H), 7.45-7.42 (m, 2H), 7.04 (s, (M, 1H), 6.34 (brs, 1H), 5.31 (s, 1H), 4.72-4.70 1H), 1.75-1.73 (m, 2H), 1.52-1.47 (m, 12H).

(R) -3,3,3-trifluoro-2-hydroxy-1- {4- [2- (6-methoxy-pyridazin- Yl} -2-methyl-propan-1-one ("A93")

(R) -3,3,3-trifluoro-2-hydroxy-1- [4- [2- (4-hydroxycyclohexyl) -2H-pyrazol-3-yl] Yl] -2-methyl-propan-1-one ("A94 &

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 35 mg (73%) as a colorless solid; (Purity 100%, Rt: 1.64 min, (M + H) 390.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.30 (d, J = 1.8 Hz, 1H), 7.06 (s, 1H), 5.99 (d, J = 1.8 Hz, 1H), 4.92-4.33 (m, 3H), 4.26-4.03 (m, 1H), 3.57-3.42 (m, 1H), 3.23-2.63 (m, 3H), 2.03-1.66 (m, 9H), 1.63-1.19 .

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- [4- (trifluoromethoxy) -phenyl] Yl] -1-piperidyl] propan-1-one ("A95 &

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 104 mg (67%) as a colorless solid; (Purity 100%, Rt: 2.31 min, (M + H) 452.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.67-7.60 (m, 3H), 7.55 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.38 (s, 1H) , 4.93-4.20 (m, 2H), 3.09-2.94 (m, 2H), 2.70-2. 54 (m, 1H), 1.89-1.74 (m, 2H), 1.61-1.47 (m, 5H).

(R) -1- [4- [2- [4- (difluoromethoxy) phenyl] -2H-pyrazol-3-yl] -1-piperidyl] -3,3,3-trifluoro Hydroxy-2-methyl-propan-1-one ("A96 &

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 139 mg (69%) as a colorless solid; (Purity 100%, Rt: 2.15 min, (M + H) 434.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.57 (d, J = 1.8 Hz, 1H), 7.56-7.14 (m, 5H), 7.02 (s, 1H), 6.39-6.27 (m, 1H), 5.02-4.14 (m, 2H), 3.06-2.91 (m, 2H), 2.64-2.53 (m, 1H), 1.86-1.72 (m, 2H), 1.68-1.37

(R) -1- {4- [2- (2,4-Difluoro-phenyl) -5-methyl-2H- pyrazol-3-yl] -piperidin- , 3-Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A97").

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 126 mg (76%) colorless solid; (Purity 99.6%, Rt: 2.10 min, (M + H) 418.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.64-7.50 (m, 2H), 7.30-7.22 (m, 1H), 7.01 (s, 1H), 6.12 (s, 1H), 4.88- 2H), 1.61-1.32 (m, 5H), 4.17 (m, 2H), 3.06-2.79 (m, 1H), 2.67-2.52 (m, 2H), 2.17 (s,

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- -1-yl] -propan-1-one ("A98").

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 259 mg (81%) as a colorless solid; (Purity 99.5%, Rt: 2.04 min, (M + H) 382.2); ¹ H NMR (400 MHz, DMSO-d ₆ )? [Ppm] 7.56-7.48 (m, 2H), 7.48-7.39 (m, 3H), 7.02 (s, 2H), 1.63-1.32 (m, 5H), 4.27 (m, 2H), 3.01-2.87 (m, 2H), 2.65-2.49

Methyl-lH-pyrazol-3-yl) -piperidin-l-yl (l- ] -Propan-1-one ("A99").

Synthesis of "A21" also resulted in positional isomers, which were separated by preparative HPLC; Yield: 30 mg (4%) colorless oil; (Purity 98.4%, Rt: 2.59 min, (M + H) 306.0); 1H (400 MHz, DMSO-d 6) δ [ppm] 7.53 (d, J = 2.0 Hz, 1H), 7.04 (s, 1H), 6.04 (d, J = 2.0 Hz, 1H), 4.70-4.60 (m 2H), 1.90-1.87 (m, 2H), 1.55-1.30 (m, IH) (m, 5 H).

(4-chloro-3-fluoro-phenyl) -2H-pyrazol-3-yl] -piperidin- Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A100").

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 91 mg (66%) as a colorless solid; (Purity 98.3%, Rt: 2.27 min, (M + H) 420.1-422.1); ¹ H NMR (500 MHz, DMSO-d ₆ )? [Ppm] 7.77 (t, J = 8.4 Hz, 1H), 7.66 (dd, J = 2H), 3.15-2.54 (m, 3H), 1.93-1.28 (m, 1H), 7.47-7.35 , 7H).

(4-chloro-phenyl) -2H-pyrazol-3-yl] -2-hydroxy-2-methyl-propan-1-one ("A101").

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 192 mg (86%) colorless solid; (Purity 100%, Rt: 2.37 min, (M + H) 436.0-440.0);

^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 7.87-7.76 (m, 2H), 7.63 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 8.6, 2.5 Hz, 1H) , 7.03 (s, 1 H), 6.38 (s, 1 H), 4.92 - 4.21 (m, 2H), 3.19 - 2.55 (m, 3H), 1.98 - 1.35 (m, 7H).

Methyl-1- {4- [1- (5-trifluoromethyl-pyridin-2-yl) -1H-pyrazole Yl] -piperidin-1-yl} -propan-1-one ("A102").

Purification by preparative HPLC; Yield: 175 mg (28%) as a pale yellow solid; (Purity 98.9%, Rt: 5.11 min, (M + H) 437.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.84 (dd, J = 1.5, 0.8 Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.33 (dd, J = 2.4, (D, J = 2.6 Hz, 1H), 4.74-4.72 (m, 1H), 4.39-4.37 (m, 2H), 1.68-1.66 (m, 2H), 2.70-2.40 (m, IH) 1.53-1.52 (m, 3 H).

(R) -1- {4- [l- (5-Chloro-pyrimidin-2- yl) -lH- pyrazol- 3- yl] -piperidin- 1 -yl} Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A103").

Purification by preparative HPLC; Yield: 16 mg (15%) colorless solid; (Purity 100%, Rt: 2.01 min, (M + H) 404.0-406.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.94 (s, 2H), 8.53 (d, J = 2.7 Hz, 1H), 7.07 (s, 1H), 6.54 (d, J = 2.7 Hz (M, 2H), 1.80 (m, IH), 4.89-4.31 (m, 2H), 3.29-3.08 -1.43 (m, 5 H).

Methyl-1- [4- (2H-pyrazol-3-yl) -piperidin- l-yl] - propan- ("A104").

Purification by preparative HPLC; Yield: 11 mg (6%) colorless solid; (Purity 100%, Rt: 1.53 min, (M + H) 292.1); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 12.68-12.29 (m, 1H), 7.68-7.27 (m, 1H), 7.03 (s, 1H), 6.06 (s, 1H), 4.84- (M, 2H), 3.24-3.04 (m, 1H), 2.99-2.65 (m, 2H), 2.00-1.84 (m, 2H), 1.67-1.40 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-1- {4- [1- (6-methoxy-pyridazin- -Piperidin-l-yl} -2-methyl-propan-l-one ("A105").

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 93 mg (51%) as a colorless solid; (Purity 98.2%, Rt: 2.04 min, (M + H) 400.1); ^{1 H NMR (500 MHz, DMSO} -d6) δ [ppm] 8.63 (d, J = 2.6 Hz, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.47 (d, J = 9.4 Hz, 1H) (M, 3H), 7.11 (s, 3H), 7.19 (s, 1H), 6.59 (d, J = 2.6 Hz, 1H), 5.05-4.25 , &Lt; / RTI &gt; 2H), 1.85-1.45 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1 - [(3S, 4S) Yl) -piperidin-1-yl] -propan-1-one ("A106").

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 13 mg (28%) as a colorless solid; (Purity 100%, Rt: 2.07 min, (M + H) 382.1); ^{1 H NMR (500 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 7.59-7.36 (m, 6H), 6.68 (s, 1H), 6.26 (d, J = 1.6 Hz, 1H), 4.59-4.42 (m, 1 H), 2.94-2.82 (m, 1H), 1.99-1.81 (m, 1H), 4.22-4.04 , 1.78-1.61 (m, 2H), 1.61-1.42 (m, 3H), 0.60 (d, J = 7.0 Hz, 3H).

(R) -3,3,3-trifluoro-l- {(3S, 4S) -4- [2- (4-fluoro- phenyl) -2H- (R) -3,3,3-trifluoro-1 - {(3R, 5S) -2-hydroxy- 4-yl) -2-hydroxy-2-methyl-propane &lt; / RTI &gt; -1-one ("A108").

107.1 / 108.1 (3S, 4S) -4- [2- (4-fluoro-phenyl) -2H-pyrazol- 3- yl] -3-methyl-piperidine- 1- carboxylic acid tert- 3-yl] -3-methyl-piperidine-1-carboxylic acid terf-butyl ester &lt; EMI ID =

(250 mg, 1.015 mmol) and tert-butoxybis (dimethylamino) methane (187.7 mg, 1.066 mmol) were added to a vial And the mixture was stirred at 100 DEG C for 45 minutes. A clear yellow solution formed. The mixture was cooled to room temperature and diluted with ethanol (2.5 mL). (4-fluoro-phenyl) -hydrazine hydrochloride (168.4 mg; 1.015 mmol) and the mixture was heated at 80 &lt; 0 &gt; C for 3 hours. The mixture was evaporated to dryness and the residue was purified by RP-flash chromatography (CombiFlashRF 200). The pure fractions were combined, the acetonitrile removed in vacuo, diluted with saturated aqueous NaHCO ₃ - solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo; Yield: 215 mg (59%) orange-red oil (cis / trans: 95/5).

210 mg of the diastereomeric mixture was separated by chiral chromatography:

SFC; Column: ChiralPak AD-H; Eluent: CO ₂ / methanol: 95/5; 220nm

yield: 108.1: 83 mg (40%), yellow oil;

107.1: 71 mg (34%), yellow oil.

107.2 (3S, 4S) -4- [2- (4-Fluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidine hydrochloride

Preparation as described for example "A32" (step 32.3).

107.3 (R) -3,3,3-trifluoro-l- {(3S, 4S) -4- [2- (4-fluoro- phenyl) -2H- Yl} -2-hydroxy-2-methyl-propan-1-one ("A107").

Preparation and purification as described in example "A32" (step 32.4); Yield: 33 mg (79%) Colorless solid; (Purity 100%, Rt: 2.1 min, (M + H) 400.1); HPLC (Chiralpak AD-H; CO ₂ / MeOH-95/5): Rt 3.32 min; ^{1 H NMR (400 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 7.56 (d, J = 1.7 Hz, 1H), 7.53-7.45 (m, 2H), 7.38-7.29 (m, 2H), 6.74 (m, 3H), 1.92 (q, d, J = 7.6 Hz, 1H) J = 11.4, 4.2 Hz, 1H), 1.78-1.66 (m, 2H), 1.62-1.51 (m, 3H), 0.62 (d, J = 7.0 Hz, 3H); [?] ^D ₂₀ = -75.4 (? 0.84).

108.2 (3R, 4R) -4- [2- (4-fluoro-phenyl) -2H-pyrazol-3-yl] -3-methyl-piperidine hydrochloride

Preparation as described in example "A32" (step 32.3).

108.3 (3R, 4R) -4- [2- (4-fluoro-phenyl) -2H-pyrazol- -Piperidin-l-yl} -2-hydroxy-2-methyl-propan-l-one ("A108").

Preparation and purification as described for example "A32" (step 32.4); Yield: 304 mg (94%) yellow foam; (Purity 100%, Rt: 2.11 min, (M + H) 400.1); HPLC (Chiralpak AD-H; CO ₂ / MeOH-95/5): Rt 2.00 min.

(R) -1- {4- [1- (3,5-Difluoro-pyridin-2-yl) -lH- pyrazol-3- yl] -piperidin- 1 -yl} , 3-Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A109").

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 30 mg (13%) colorless solid; (Purity 100%, Rt: 2.05 min, (M + H) 405.1); ^{1 H NMR (500 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 8.51 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 2.6, 0.9 Hz, 1H), 8.28 (ddd, J 2H), 3.34-3.13 (m, 1H), 3.12 (d, J = 2.6 Hz, 3.00 (m, 1H), 2.98-2.78 (m, 1H), 2.08-1.97 (m, 2H), 1.77-1.53 (m, 5H).

(3S, 4S) -4- [2- (4-methoxy-phenyl) -2H-pyrazol-3-yl] -3-methyl Yl} -2-hydroxy-2-methyl-propan-1-one ("A110").

Preparation and purification as described for example "A32" (step 32.4); Yield: 36 mg (53%) as a colorless solid; (Purity 100%, Rt: 2.08 min, (M + H) 412.1); ^{1 H NMR (400 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 7.49 (d, J = 1.9 Hz, 1H), 7.42-7.23 (m, 2H), 7.17-6.93 (m, 2H), 6.69 (s, 1H), 6.22 (d, J = 1.9 Hz, IH), 4.49 (d, J = 13.2 Hz, IH), 4.29-4.04 (m, 2H), 2.96-2.83 (m, 1H), 2.01-1.81 (m, 1H), 1.81-1.61 7.0 Hz, 3H).

Methyl-1 - ((R) -3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl) -piperidine- Yl] -pyrazol-1-yl} -benzonitrile ("A111").

Preparation and purification as described in example "A32" (step 32.4); Yield: 32 mg (56%) as a colorless solid; (Purity 100%, Rt: 2.06 min, (M + H) 407.1); ^{1 H NMR (400 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 7.95 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 1.7 J = 11.1 Hz, 1H), 6.70 (s, 1H), 6.33 (d, J = 1.6 Hz, 1H), 4.66-4.46 2H), 1.53 (s, 3H), 0.58 (m, &lt; RTI ID = 0.0 &gt; (d, J = 7.0 Hz, 3 H).

(2R) -1- [4- [2- (5-fluoro-2-pyridyl) -2H-pyrazol-3-yl] -1-piperidyl] -3,3,3-trifluoro -2-hydroxy-2-methyl-propan-1-one ("A112").

Purification by RP-flash chromatography (CombiFlashRF 200); Yield: 189.5 mg (87%) colorless solid; (Purity 100%, Rt: 2.09 min, (M + H) 387.1); ^{1 H NMR (500 MHz, DMSO} -d 6) δ [ppm] 8.52 (d, J = 3.0 Hz, 1H), 7.99-7.91 (m, 1H), 7.85 (dd, J = 9.0, 4.0 Hz, 1H) 2H), 3.76-3.59 (m, 1H), 3.20-2.53 (m, 1H), 7.65 (d, J = , 2H), 2.02-1.89 (m, 2H), 1.68-1.32 (m, 5H).

(R) -3,3,3-Trifluoro-1 - {(3S, 4S) -4- [2- (6-methoxy- Methyl-piperidin-l-yl} -2-hydroxy-2-methyl-propan-l-one ("A113").

Preparation and purification as described for example "A32" (step 32.4); Yield: 68 mg (77%) colorless solid; (Purity 100%, Rt: 1.97 min, (M + H) 413.1); ^{1 H NMR (400 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 8.23 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.7, 2.7 Hz, 1H), 7.56 (d, J = 1.7, 1H), 6.94 (d, J = 8.7 Hz, IH), 6.70 (brs, IH), 6.27 (d, J = 1.7 Hz, 1H), 4.58-4.43 (m, 3H), 3.94 (m, 3H), 3.94 (m, d, J = 7.0 Hz, 3H).

(R) -3,3,3-Trifluoro-2-hydroxy-1- [4- (1-isobutyl-1H-pyrazol-3- yl) -piperidin- Methyl-propan-1-one ("A114").

Synthesis of T "A76 " also resulted in positional isomers, which were separated by preparative HPLC; Yield: 42 mg (11%) light brown gum; (Purity 96.0%, Rt: 3.77 min, (M + H) 348.3); ^{1 H NMR (400 MHz, CDCl} 3): δ [ppm] 7.28-7.27 (m, 1H), 6.03 (d, J = 2.2 Hz, 1H), 5.57 (brs, 1H), 4.60-4.45 (m, 2H 2H), 3.04-2.96 (m, 1H), 2.21-2.14 (m, 1H), 2.09-2.02 (m, 2H), 3.87 (d, J = 7.3 Hz, 2H) 1.73-1.68 (m, 5H), 0.90 (d, J = 6.80 Hz, 6H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- {4- [2- -Yl] -piperidin-l-yl} -propan-1-one ("A115").

Purification of flash column chromatography; Yield: 75 mg (23%) brown gum; (Purity 99.4%, Rt: 3.92 min, (M + H) 373.0); ^{1 H NMR (400 MHz, MeOH} -d 4) δ [ppm] 7.68 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 1.2 Hz, 1H), 6.38 (d, J = 1.6 Hz, 1H ), 5.09-5.07 (m, IH), 4.63-4.60 (m, IH), 3.72-3.66 (m, IH), 3.15-3.13 , 3H), 2.12-2.09 (m, 2H), 1.72-1.63 (m, 5H).

(R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- {4- [2- (tetrahydro- ] -Piperidin-1-yl} -propan-1-one ("A116").

Purification by preparative HPLC and finally grinding with hexane; Yield: 120 mg (28%) as a pale yellow solid; (Purity 99.1%, Rt: 3.09 min, (M + H) 376.3); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.35 (d, J = 1.4 Hz, 1H), 7.08 (s, 1H), 6.02 (s, 1H), 4.80-4.78 (m, 1H) 2H), 3.10-3.06 (m, 2H), 2.73-2.66 (m, 1H), 2.12 (m, -2.01 (m, 2H), 1.87-1.84 (m, 2H), 1.73-1.71 (m, 2H), 1.52-1.40 (m, 5H).

(R) -l- [4- (2-benzothiazol-2-yl-2H-pyrazol-3- yl) -piperidin- l-yl] -3,3,3-trifluoro- -Hydroxy-2-methyl-propan-1-one ("A117").

Purification by column chromatography; Yield: 150 mg (49%) as a pale yellow solid; (Purity 99.1%, Rt: 5.10 min, (M + H) 425.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.08 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H 1H), 7.54-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.11 ), 4.05-4.03 (m, 1H), 3.20-3.18 (m, 1H), 2.77-2.75 (m, 1H), 2.17-2.15 (m, 2H), 1.70-1.

(R) -3,3,3-Trifluoro-1 - {(3S, 4S) -4- [2- (5-fluoro-pyridin- Methyl-piperidin-l-yl} -2-hydroxy-2-methyl-propan-l-one ("A118").

Preparation and purification as described for example "A32" (step 32.4); Yield: 63 mg (77%) colorless solid; (Purity 100%, Rt: 2.16 min, (M + H) 401.1); ^{1 H NMR (400 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 8.49 (d, J = 2.9 Hz, 1H), 7.91 (td, J = 8.5, 2.9 Hz, 1H), 7.85 (dd, J = 9.0, 4.2 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 6.73 (s, 1H), 6.34 / 6.32 (2 x d, J = 1.5 Hz, 1H, 2H), 2.23-2.11 (m, 1H), 2.09-8.30 (m, 1H), 4.94-4.61 (m, 1.91 (m, 1H), 1.79-1.67 (m, 1H), 1.60 / 1.58 (2 xs, 3H, ratio = 10: 1, mixture of rotamers), 0.71-0.61 (m, 3H).

Yl} -3-methyl-piperidin-l-yl} -3 (3S, 4S) -4- [2- (4-chloro-phenyl) , 3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A119").

Preparation and purification as described for example "A32" (step 32.4); Yield: 140 mg (88%) as a colorless solid; (Purity 99.5%, Rt: 2.25 min, (M + H) 416.1-418.1); ^{1 H NMR (400 MHz, DMSO} -d 6) d ppm] 7.69-7.56 (m, 3H), 7.57-7.47 (m, 2H), 7.13-6.84 (m, 1H), 6.51-6.11 (m, 1H) 2H), 1.52 (s, 3H), 0.71-0.41 (m, 3H), 1.94-1.61 (m, 3H).

(R) -3,3,3-Trifluoro-2-hydroxy-1 - {(3S, 4S) -4- [2- (4-hydroxy- cyclohexyl) -2H- Yl} -2-methyl-propan-1-one ("Al20").

Preparation and purification as described in example "A32" (step 32.4); Yield: 28 mg (73%) colorless solid; (Purity 100%, Rt: 1.75 min, (M + H) 404.2); ^{1 H NMR (400 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 7.33 (d, J = 1.6 Hz, 1H), 6.74 (s, 1H), 5.96 (d, J = 1.6 Hz, 1H), (M, 1H), 4.42-4.30 (m, 1H), 4.19-4.04 (m, 2H), 3.96-3.84 , 2H), 2.12-2.00 (m, 1H), 2.00-1.75 (m, 3H), 1.70-1.61 (m, 3H), 1.58 , &Lt; / RTI &gt; J = 7.0 Hz, 3H).

(R) -3,3,3-Trifluoro-2-hydroxy-1 - {(3S, 4S) -4- [2- (4-hydroxy- cyclohexyl) -2H- Yl} -2-methyl-propan-1-one ("A121").

Preparation and purification as described for example "A32" (step 32.4); Yield: 18 mg (63%) colorless solid; (Purity 96%, Rt: 1.71 min, (M + H) 404.2); ^{1 H NMR (400 MHz, DMSO} -d 6, 90 ℃) δ [ppm] 7.32 (d, J = 1.7 Hz, 1H), 6.74 (s, 1H), 5.96 (d, J = 1.7 Hz, 1H), 1H), 4.40-4.32 (m, 1H), 4.32-4.24 (m, 1H), 4.19-4.07 (M, 2H), 3.20-3.09 (m, 1H), 2.11-1.84 (m, 6H), 1.82-1.68 -1.34 (m, 2H), 0.65 (d, J = 7.0 Hz, 3H).

(R) -3,3,3-Trifluoro-2-hydroxy-1- [4- (2-isoxazol- Yl] -2-methyl-propan-1-one ("A122").

Purification by preparative HPLC; Yield: 180 mg (68%) light brown gum; (Purity 98.8%, Rt: 3.68 min, (M + H) 359.0); ¹ H NMR (400 MHz, DMSO-d ₆ )? [Ppm] 9.06 (d, J = 1.8 Hz, 1H), 7.77 1H), 6.46 (d, J = Hz, IH), 4.82-4.80 (m, IH), 4.48-4.46 (m, 1H), 2.67-2.66 (m, 1H), 1.97-1.95 (m, 2H), 1.60-1.45 (m, 5H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- (2- Yl] -propan-1-one ("A123").

Purification by flash column chromatography; Yield: 28 mg (40%) as a pale yellow solid; (Purity 96.6%, Rt: 3.11 min, (M + H) 370.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 9.20 (dd, J = 4.76, 1.4 Hz, 1H), 8.10 (dd, J = 8.9, 1.4 Hz, 1H), 7.88 (dd, J = 1H), 7.76 (d, J = 1.7 Hz, 1H), 6.47 (s, 1H), 4.77-4.75 (m, 1H), 4.44-4.42 (m, 1H), 3.82-3.78 1H), 3.06-2.99 (m, 1H), 2.78-2.76 (m, 1H), 2.01-1.98 (m, 2H), 1.57-1.50 (m, 5H).

(R) -3,3,3-Trifluoro-1- {4- [3- (4-fluoro-phenyl) 2-hydroxy-2-methyl-propan-1-one ("A124").

Preparation as described for example "A65 &quot;. Yield: 30 mg (21%) as a pale yellow solid; (Purity 97.8%, Rt: 2.90 min, (M + H) 386.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.68 (s, 1H), 7.53-7.50 (m, 2H), 7.42-7.38 (m, 2H), 7.03 (s, 1H), 6.86 ( (m, 2H), 1.80-1.30 (m, 2H), 1.85-1.30 (m, 1.57-1.29 (m, 6H).

(4-chloro-phenyl) -3H-imidazol-4-yl] -Hydroxy-2-methyl-propan-1-one ("A125").

Preparation as described for example "A65 &quot;. Yield: 27 mg (18.5%) as a pale yellow solid; (Purity 94.1%, Rt: 3.22 min, (M + H) 402.0-404.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.70 (d, J = 0.8 Hz, 1H), 7.63-7.61 (m, 2H), 7.51-7.48 (m, 2H), 7.03 (s, 1H), 6.87 (s, 1H), 4.80-4.60 (m, 1H), 4.47-4.29 (m, 1H), 3.02-2.89 m, 2H), 1.60-1.34 (m, 6H).

(4-chloro-2-fluoro-phenyl) -3H-imidazol-4- Trifluoro-2-hydroxy-2-methyl-propan-1-one ("A126").

Preparation as described for example "A65 &quot;. Yield: 15 mg (9%) as a pale yellow solid; (Purity 99.1%, Rt: 3.19 min, (M + H) 420.0-422.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.78-7.75 (m, 1H), 7.69 (s, 1H), 7.60 (t, J = 8.4 Hz, 1H), 7.48 (d, J = (M, 1H), 2.63-2.55 (m, IH), 7.89 (s, (m, 1H), 1.79-1.62 (m, 2H), 1.59-1.30 (m, 5H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- {4- [3- (4-trifluoromethyl- phenyl) ] -Piperidin-l-yl} -propan-1-one ("A127").

Preparation as described for example "A65 &quot;. Yield: 27 mg (13.5%) as a pale yellow solid; (Purity 97.5%, Rt: 3.46 min, (M + H) 436.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.94 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.03 (s 2H), 2.63-2.52 (m, IH), 1.81-1.65 (m, IH) (m, 2H), 1.59 - 1.39 (m, 5H).

(R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- Propan-1-one ("A128").

128.1  4- (3-Phenyl-isoxazol-4-yl) -piperidine-l-carboxylic acid tert-butyl ester

In a microwave vessel, 1-Boc-4-ethynylpiperidine (100.0 mg, 0.468 mmol) and (Z) -N-hydroxybenzimidyl chloride (88.4 mg, 0.515 mmol) were dissolved in dry 1,2- Ethane (4.50 mL), triethylamine (81.1 [mu] L; 0.585 mmol) was added and the mixture was degassed with nitrogen. Chloro (1,5-cycloocta-diene) (pentamethylcyclopentadienyl) ruthenium (9,17 mg; 0.023 mmol) was added to the colorless suspension. The reaction was degassed again with nitrogen and stirred at room temperature for 14 hours. The reaction mixture was evaporated and the residue was purified by flash chromatography (CombiFlash RF 200); Yield: 122 mg (78%) yellow oil.

128.2 4- (3-Phenyl-isoxazol-4-yl) -piperidine hydrochloride

HCl in dioxane (4.0 M; 4.58 mL; 18.315 mmol) was added to a solution of 4- (3-phenyl-isoxazol-4-yl) -piperidin- Carboxylic acid tert-butyl ester (122.0 mg; 0.366 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated in vacuo and the residue was used without further purification.

128.3 (R) -3,3,3-Trifluoro-2-hydroxy-2-methyl-1- [4- Propan-1-one ("A128").

Coupling reactions were carried out as described above; Yield: 79 mg (58%) as a colorless solid; (Purity 99.1%, Rt: 2.21 min, (M + H) 369.1); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.88 (d, J = 0.7 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.59 - 7.48 (m, 3H), 7.00 (s, 1H), 2.94-2.56 (m, 1H), 4.93-4.56 (m, 1H), 4.56-4.16 1.74 (m, 2H), 1.61-1.31 (m, 5H).

(R) -3,3,3-Trifluoro-1- {4- [3- (4-fluoro- phenyl) -isoxazol-4-yl] -piperidin- Hydroxy-2-methyl-propan-1-one ("A129").

Manufactured as described in "A126". Yield: 61 mg (37%) as a colorless solid; (Purity 98.0%, Rt: 2.25 min, (M + H) 387.1); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.96-8.78 (m, 1H), 7.78-7.60 (m, 2H), 7.46-7.27 (m, 2H), 7.00 (s, 1H), (M, 1H), 2.93-2.53 (m, 1H), 1.92-1.75 (m, , &Lt; / RTI &gt; 2H), 1.61-1.30 (m, 5H).

(R) -1- {4- [3- (2,4-Difluoro-phenyl) -3H-imidazol-4-yl] -piperidin- 1 -yl} -3,3,3-tri Fluoro-2-hydroxy-2-methyl-propan-1-one ("A130").

Prepared as described in example "A65 &quot;. Yield: 2 mg (2%) as a pale yellow solid; (Purity 94.6%, Rt: 2.91 min, (M + H) 404.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.69-7.58 (m, 3H), 7.32-7.27 (m, 1H), 7.04 (s, 1H), 6.88 (s, 1H), 4.80- 2H), 1.56-1.37 (m, 5H, m, 2H), 4.50 (m, ).

(R) -3,3,3-Trifluoro-2-hydroxy-1- {4- [3- (4- methoxy- phenyl) -3H- imidazol-4-yl] -piperidin- Yl} -2-methyl-propan-1-one ("A131").

Prepared as described in example "A65 &quot;. Yield: 12 mg (15%) as a pale yellow solid; (Purity 94.3%, Rt: 2.97 min, (M + H) 398.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.60 (s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.02 (s 1H), 6.82 (brs, 1H), 4.76-4.51 (m, 1H), 4.45-4.20 (m, 1H), 3.81 (s, 3H), 3.03-2.83 , &Lt; / RTI &gt; 1H), 1.79-1.61 (m, 2H), 1.57-1.29 (m, 6H).

(R) -3,3,3-Trifluoro-1- {4- [3- (2-fluoro- phenyl) 2-Hydroxy-2-methyl-propan-1-one ("A132").

Prepared as described in example "A65 &quot;. Yield: 9 mg (2%) as a pale yellow solid; (Purity 97.1%, Rt: 2.76 min, (M + H) 386.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.71 (s, 1H), 7.63-7.49 (m, 3H), 7.41-7.37 (m, 1H), 7.02 (s, 1H), 6.90 ( 2H), 2.63-2.59 (m, 1H), 1.78-1.60 (m, 2H), 4.80-4.52 (m, 1.59-1.32 (m, 5 H).

(R) -3,3,3-trifluoro-2-hydroxy-1- {4- [3- (6-methoxy- Piperidin-1-yl} -2-methyl-propan-1-one ("A133").

Prepared as described in example "A65 &quot;. Yield: 20 mg (18%) as a pale yellow solid; (Purity 99.6%, Rt: 2.67 min, (M + H) 399.0); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 8.27 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 8.7, 5.7 Hz, 1H), 7.69 (s, 1H), 7.03 (s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.88 (s, 1H), 4.78-4.60 3.10-2.88 (m, 2H), 2.80-2.70 (m, 1H), 1.80-1.65 (m, 2H), 1.60-1.32 (m, 5H).

(R) -3,3,3-Trifluoro-1- {4- [3- (2-fluoro-4-methoxy- phenyl) -3H-imidazol- Yl} -2-hydroxy-2-methyl-propan-1-one ("A134").

Prepared as described in example "A65 &quot;. Yield: 20 mg (13%) as a pale yellow solid; (Purity 96.7%, Rt: 2.99 min, (M + H) 416.2); ^{1 H NMR (400 MHz, DMSO} -d 6) δ [ppm] 7.63 (s, 1H), 7.48-7.44 (m, 1H), 7.13 (dd, J = 12.0, 7.4 Hz, 1H), 7.03 (s, 1H), 6.93 (d, J = 8.4, 5.6 Hz, 1H), 6.87 (s, 1H), 4.80-4.58 (m, 2H), 1.72-1.69 (m, 2H), 1.60-1.33 (m, 5H).

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- Pyrazol-3-yl] -1-piperidyl] propan-1-one ("A135").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- Piperidyl] propan-1-one ("A136").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- (5-methyl-1,3,4-thiadiazol- Pyrazol-3-yl] -1-piperidyl] propan-1-one ("A137").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- (5-methyl-1,3,4-oxadiazol- Pyrazol-3-yl] -1-piperidyl] propan-1-one ("A138").

;

;

2-methyl-1- [4- [2- (2-methylpyrimidin-5-yl) pyrazol-3-yl] - 1-piperidyl] propan-1-one ("A139").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- 1-piperidyl] propan-1-one ("A140").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- (5-methylpyrazin- - piperidyl] propan-1-one ("A141").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- Piperidyl] propan-1-one ("A142").

;

;

(2R) -1- [4- [2- [4- (1,1-difluoroethyl) phenyl] pyrazol-3-yl] -1- piperidyl] -3,3,3-trifluoro 2-hydroxy-2-methyl-propan-1-one ("A143").

;

;

(3R, 4S) -4- [2- (3,5-difluoro-2-pyridyl) pyrazol-3-yl] -3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A144").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1 - [(3S, 4S) Yl) pyrazol-3-yl] -1-piperidyl] propan-1-one ("A145").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1- [4- [2- Pyrazol-3-yl] -1-piperidyl] propan-1-one ("A146").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-2-methyl-1 - [(3S, 4S) -3-methyl-4- [2- (2,2,2- -1,1-dimethyl-ethyl) pyrazol-3-yl] -1-piperidyl] propan-1-one ("A147").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-1 - [(3S, 4S) -4- [2- [4- (1 -hydroxy- ] -Pyrazol-3-yl] -3-methyl-1-piperidyl] -2-methyl-propan-1-one ("A148").

;

;

(3R, 4S) -4- [3- (4-fluorophenyl) -1,2,4-triazol-4-yl] - 3-methyl-1-piperidyl] -2-hydroxy-2-methyl-propan-1-one ("A149").

;

;

(2R) -1 - [(3R, 4S) -4- [3- (2,4-difluorophenyl) -1,2,4- triazol- Peridyl] -3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one ("A150").

;

;

(2R) -3,3,3-trifluoro-2-hydroxy-1- [4- [3- [4- (1 -hydroxy- Yl] -1-piperidyl] -2-methyl-propan-1-one ("A151").

;

;

(2R) -3,3,3-trifluoro-1 - [(3S, 4S) -4- [3- (4- fluorophenyl) imidazol- Peridyl] -2-hydroxy-2-methyl-propan-1-one ("A152").

;

;

(2R) -3,3,3-trifluoro-1- [4- [3- (4-fluorophenyl) -2-methyl-imidazol- -Hydroxy-2-methyl-propan-1-one ("A153").

;

;

(2R) -3,3,3-trifluoro-1- [4- [3- (4-fluorophenyl) -2- (hydroxymethyl) imidazol- ] -2-hydroxy-2-methyl-propan-1-one ("A154").

;

;

(2R) -3,3,3-Trifluoro-1- [4- [3- (4-fluorophenyl) -2-methoxy- Hydroxy-2-methyl-propan-1-one ("A155 &

.

.

Pharmacodynamic data

Table 1. Inhibition of PDHK of some representative compounds of formula I

The compounds shown in Table 1 are particularly preferred compounds according to the present invention.

The following examples relate to pharmaceuticals:

Example A: Injection vial

A solution of 100 g of the active ingredient of formula I and 5 g of disodium hydrogen phosphate in 3 l of secondary distilled water was adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred to the injection vial and frozen under sterile conditions Dried and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

Example B: Suppository

A mixture of 20 g of the active ingredient of formula (I), 100 g of soy lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

1 g of the active ingredient of formula I in 940 ml of secondary distilled water, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ .12 H ₂ O and 0.1 g of benzalkonium chloride Solution. The pH is adjusted to 6.8, the solution is made up to 1 l and sterilized by irradiation with radiation. These solutions can be used in the form of eye drops.

Example D: Ointment

500 mg of the active ingredient of formula I are mixed under sterile conditions with 99.5 g of Vaseline.

Example E: refine

A mixture of 1 kg of the active ingredient of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate was compressed in a conventional manner such that each tablet contains 10 mg of active ingredient &Lt; / RTI &gt;

Example F: Party

The tablets were compressed analogously to Example E followed by the addition of sucrose, potato starch, talc, tragacanth and dye Coating is used in the usual manner.

Example G: capsule

2 kg of the active ingredient of formula I are introduced into the hard gelatine capsules in the usual manner so that each capsule contains 20 mg of the active ingredient.

Example H: ample

A solution of 1 kg of active ingredient of formula I in 60 l of secondary distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims (13)

Compounds of formula (I), and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures of all ratios thereof:

[Wherein,
R is pyrazol-diyl, imidazol-diyl, isoxazol-diyl or triazol-diyl, each of which is unsubstituted or monosubstituted with R ² ,
R ¹ represents (CH ₂ ) _n Ar, (CH ₂ ) _n Het, A or Cyc,
R ² represents A ', methoxy, hydroxymethyl, COOA', CN, COOH, CONH ₂ or OH,
R ³ represents H, A ', COOA' or CN,
Ar is phenyl, which is unsubstituted, or Hal, A, CN, OA, [C (R 5) 2] p OH, [C (R 5) 2] p N (R 5) 2, NO 2, [C _{^{(R 5) 2] p COOR}} 5, NR 5 COA, NR 5 SO 2 A, [C (R 5) 2] p SO 2 n (R 5) 2, S (O) n A, O [C (R _{^{5) 2] m N (R}} 5) 2, NR 5 COOA, NR 5 CON (R 5) 2 , and / or mono to COA -, di-, tri-, tetra- or penta-substituted,
Het is a 1 to 4 N, O and / or mono with a S atom-or bicyclic saturated, unsaturated or aromatic heterocycle, which is unsubstituted or Hal, A, CN, OA, [C (R 5) 2] ^{_{p OH, [C (R 5}} ) 2] p N (R 5) 2, NO 2, [C (R 5) 2] p COOR 5, NR 5 COA, NR 5 SO 2 A, [C (R 5) _{2] p SO 2 n (R} 5) 2, S (O) n A, O [C (R 5) 2] m n (R 5) 2, NR 5 COOA, NR 5 CON (R 5) 2 , and / Or mono-or disubstituted with COA,
Cyc is a cyclic alkyl having 3, 4, 5, 6 or 7 C atoms, which is unsubstituted or mono-substituted with OH,
A represents a non-branched or branched alkyl having 1 to 10 C atoms, wherein one or two non-adjacent CH- and / or CH ₂ groups may be replaced by N-, O- and / or S - the atoms may be replaced and / or 1-7 H atoms may be replaced by R ⁴ ,
R ⁴ represents F, Cl or OH,
R ⁵ represents H or A '
A 'represents a non-branched or branched alkyl having 1-6 C atoms, where 1-5 H atoms may be replaced by F,
Hal represents F, Cl, Br or I,
m represents 1, 2, 3 or 4,
n represents 0, 1 or 2,
p represents 0, 1, 2, 3 or 4]. The method according to claim 1,
R ² is A ', methoxy or hydroxymethyl, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures thereof in all ratios. 3. The method according to claim 1 or 2,
R &lt; ³ &gt; is H or A &lt; 1 &gt;, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures thereof in all ratios. 4. The method according to any one of claims 1 to 3,
Ar is unsubstituted or represents a mono-, di-, tri-, tetra- or penta substituted phenyl with Hal, A, CN and / or OA, and pharmaceutically acceptable salts, tautomers and stereoisomers , And mixtures thereof in all ratios. 5. The method according to any one of claims 1 to 4,
Het is selected from pyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, Each of which is unsubstituted or mono-or disubstituted with Hal, A, CN and / or OA, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, Isomers, and mixtures thereof in all ratios. The method according to claim 1,
R is pyrazol-diyl, imidazol-diyl, isoxazol-diyl or triazol-diyl, each of which is unsubstituted or monosubstituted by R ² ,
R ¹ represents (CH ₂ ) _n Ar, (CH ₂ ) _n Het, A or Cyc,
R ² represents A ', methoxy or hydroxymethyl,
R ³ represents H or A '
Ar represents unsubstituted or mono-, di-, tri-, tetra- or penta substituted phenyl with Hal, A, CN and / or OA,
Het is selected from pyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, Each of which is unsubstituted or mono- or di-substituted with Hal, A, CN and / or OA,
Cyc is a cyclic alkyl having 3, 4, 5, 6 or 7 C-atoms, which is unsubstituted or mono-substituted with OH,
A represents a non-branched or branched alkyl having 1 to 10 C-atoms, wherein one or two non-adjacent CH- and / or CH ₂ - groups may be replaced by N-, O- and / or S- And / or 1-7 H atoms may be replaced by R ⁴ ,
R ⁴ represents F, Cl or OH,
A 'represents a non-branched or branched alkyl having 1-6 C atoms, where 1-5 H atoms may be replaced by F,
Hal represents F, Cl, Br or I,
n is 0, 1 or 2, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures thereof in all ratios. 10. A compound according to claim 1, selected from the group consisting of: and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures thereof in all ratios:

. 10. A process for the preparation of a compound of formula I according to any one of claims 1 to 7, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, characterized by:
A compound of formula II:

Wherein R, R &lt; ¹ &gt; and R &lt; ³ &gt; have the meanings indicated in claim 1,
With a compound of formula III: &lt; EMI ID =

[Wherein L represents Cl, Br, I or a free or reactive functional modified OH group]
/ RTI &gt; and /
Converting the base or acid of formula (I) into one of its salts. A medicament comprising at least one compound of formula I and / or a pharmaceutically acceptable salt, tautomer and stereoisomer thereof, and mixtures thereof in any ratio, and optionally a pharmaceutically acceptable carrier, excipient or vehicle. For the treatment and / or prophylaxis of cancer, diabetes, cardiac ischemia, insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, heart failure, cardiomyopathy, myocardial ischemia, hyperlipidemia, mitochondrial diseases, mitochondrial myopathies , And pharmaceutically acceptable salts, tautomers and stereoisomers thereof, and mixtures of all ratios thereof. 11. The method of claim 10, further comprising administering an effective amount of at least one compound selected from the group consisting of head, neck, eye, oral cavity, throat, esophagus, bronchus, larynx, pharynx, thoracic, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, Or a disease selected from the group of cancers of the reproductive organs, skin, thyroid, blood, lymph node, kidney, liver, pancreas, brain, central nervous system, solid tumors and blood cancerous tumors. At least one compound of formula I and / or a pharmaceutically acceptable salt, tautomer and stereoisomer thereof, and mixtures thereof in all ratios, and at least one additional pharmaceutical active ingredient. Set (kit) consisting of the following individual packs:
(a) an effective amount of a compound of formula I and / or a pharmaceutically acceptable salt, tautomer, and stereoisomer thereof, and mixtures thereof in all ratios,
And
(b) an effective amount of an additional pharmaceutical active ingredient.